Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

Energy Technology Data Exchange (ETDEWEB)

Corn, Paul G., E-mail: pcorn@mdanderson.org [Department of Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Song, Danny Y. [Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (United States); Heath, Elisabeth; Maier, Jordan [Karmanos Cancer Institute, Wayne State University, Detroit, Michigan (United States); Meyn, Raymond [Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Kuban, Deborah [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); DePetrillo, Thomas A. [Department of Radiation Oncology, Tufts Medical Center, Boston, Massachusetts (United States); Mathew, Paul, E-mail: pmathew@tuftsmedicalcenter.org [Department of Hematology-Oncology, Tufts Medical Center, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States)

2013-07-01

Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.

CENTRAL SEROUS CHORIORETINOPATHY IN POSTMENOPAUSAL WOMEN RECEIVING EXOGENOUS TESTOSTERONE.

Science.gov (United States)

Conway, Mandi D; Noble, Jason A; Peyman, Gholam A

2017-01-01

Central serous chorioretinopathy (CSR) is a serous detachment of the neurosensory retina commonly associated with male sex, Type-A personality and corticosteroid use. Exogenous administration of androgens and development of CSR in men has been reported. Only one case of CSR in a postmenopausal woman receiving exogenous androgen therapy has been reported. The authors describe three cases of chronic CSR in postmenopausal women receiving exogenous testosterone therapy. Diagnosis was based on characteristic clinical, fluorescein angiographic, and optical coherence tomography findings. The three women were being treated with exogenous testosterone and progesterone therapy for symptoms of menopause and libido loss. Average age at presentation was 54.7 years (53-56 years), average duration of exogenous androgen use was 61 months (36-87 months), with average 19.7-month follow-up. Resolution of symptoms seemed correlated with cessation of androgen use despite treatment with oscillatory photodynamic therapy and intravitreal pharmacotherapy with antivascular endothelial growth factor agents. Exogenous testosterone is increasingly prescribed for menopausal symptoms and libido loss. Treatment with oscillatory photodynamic therapy, supplemental bevacizumab intravitreal pharmacotherapy, and cessation of exogenous androgen therapy was successful in three cases of chronic, therapy-resistant CSR. Ophthalmologists should inquire about androgen usage in patients who present with CSR, especially in the setting of therapy resistance.

[Expression of receptors of estrogens and androgens in the testicular appendices].

Science.gov (United States)

Paredes Esteban, R M; Luque Barona, R J; Velasco Sánchez, B; Rodríguez Vargas, J; Lorite, A; García Ruiz, M

2008-07-01

The appendices or hidátides of the testicle are structures that are considered an embryonic rest. In testicular hidátide estrogen receivers have been demonstrated but in the epididimys the results vary. Has been theorized that the elevation of the estrogen levels in the puberty can produce an inflammation and torsion of hidátide, nevertheless, in the epididimys in which the estrogen expression is not clear (and also they are twisted) the theory is put in doubt. This controversy takes us to the accomplishment of this work. A prospective study is made in 20 testicular appendices, of which 7 from the epididimys are extirpated of patients to whom an escrotal exploration is made in the development of surgery of processes of the inguino-escrotal channel (hidroceles, hernias). Optical microscopy and inmunohistoquímical study are analyzed by means of using prediluted monoclonales antibodies, for receivers of estrogens, androgens and proliferative index. The results were proceed and analyzed by means of SPSS statistical program. All hidátides, testicular and from the epididimarys expressed receivers for estrogens without significant difference among them, not existing differences as far as the location of receiving sayings within the three compartments of hidátide. The number of estrogen receivers was in relation to the age of the patient. Only hidátides from the epididimys fundamentally expressed receivers of located androgens and at level of ductus. We have not found significant relation between the proliferative index and the expression of estrogen receivers. The proliferative index was more elevated at level of ductus. 1) As much the testicular appendices as those from the epididimays expressed receivers of estrogens at level of the three compartments. It makes think about a same embryonic origin, although only the epididimal ones expressed androgen receivers. 2) the observation of estrogen receivers in both types of hidátides, as well as the relation of the

AR mutations in 28 patients with androgen insensitivity syndrome (Prader grade 0-3).

Science.gov (United States)

Wang, Yi; Gong, Chunxiu; Wang, Xiou; Qin, Miao

2017-07-01

We investigated the androgen receptor (AR) gene mutation profiles of Chinese patients exhibiting severe androgen insensitivity syndrome (AIS) phenotypes. The present study enrolled 28 patients with genetically diagnosed AIS, who presented with severe phenotypes (Prader grade 0-3). Patients and some family members were screened via amplification and sequencing of their AR exons 1-8, including the corresponding intronic flanking regions. Luteinizing (LH), follicle-stimulating (FSH), and testosterone (T) hormone levels were found to be slightly, but not significantly, higher in patients with complete androgen insensitivity syndrome (CAIS) than in patients with partial androgen insensitivity syndrome (PAIS) (P>0.05). We identified 24 different AR mutations, including 12 that were novel. Ten patients (cases 2, 3, 10, 28, 11, 12, 19, 20, 24, and 25) were found to carry five recurrent mutations (p.Y572S, p.P914S, p.S176R, p.Y782N, and p.R841H); of these, p.Y572S, p.S176R, and p.Y782N were novel. Among the mutations identified in patients with CAIS, six (66.7%) were characterized as single-nucleotide missense mutations, and six (66.7%) were found to be located in the AR ligand-binding domain (LBD). Among the mutations identified in patients with PAIS, 15 (93.8%) were found to be missense, and 11 (68.8%) were found to be located in the LBD. Patients 10 and 28 were determined to harbor the same missense mutation (p.P914S), but were diagnosed with CAIS and PAIS, respectively. Sex hormone levels were slightly, but not significantly, elevated in patients with CAIS compared to those with PAIS. Missense mutations spanning AR exons 1-8 were the predominant form of identified mutations, and these were mostly located in the AR LBD. Approximately 50% of the identified mutations were novel, and have enriched the AR gene-mutation database. Patients harboring identical mutations were in some instances found to exhibit divergent phenotypes.

Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime

International Nuclear Information System (INIS)

Martinez, Alvaro A.; Demanes, D. Jeffrey; Galalae, Razvan; Vargas, Carlos; Bertermann, Hagen; Rodriguez, Rodney; Gustafson, Gary; Altieri, Gillian; Gonzalez, Jose

2005-01-01

Purpose: High-dose radiotherapy, delivered in an accelerated hypofractionated course, was utilized to treat prostate cancer. Therapy consisted of external beam radiotherapy (EBRT) and transrectal ultrasound (TRUS)-guided conformally modulated high-dose rate (HDR) brachytherapy. The purpose of this report is (1) to assess long-term comparative outcomes from three trials using similar accelerated hypofractionated regimes; and (2) to examine the long-term survival impact of a short course of ≤6 months adjuvant/concurrent androgen deprivation when a very high radiation dose was delivered. Methods and Materials: Between 1986 and 2000, 1,260 patients were treated at three institutions with pelvic EBRT (36-50 Gy) integrated with HDR prostate brachytherapy. The total dose including brachytherapy was given over 5 weeks. The biologic equivalent EBRT dose ranged between 90 and 123 Gy (median, 102 Gy) using an α /β of 1.2. Patient eligibility criteria included a pretreatment prostate-specific antigen ≥10, Gleason score ≥7, or clinical stage ≥T2b. A total of 1,260 patients were treated, and 934 meet the criteria. Kiel University Hospital treated 198 patients; William Beaumont Hospital, 315; and California Endocurietherapy Cancer Center, 459 patients. Brachytherapy dose regimes were somewhat different between centers and the dose was escalated from 5.5 x 3 to 15 Gy x 2 Gy. Patients were divided for analysis between the 406 who received up to 6 months of androgen deprivation therapy and the 528 patients who did not. All patients had a minimum follow-up of 18 months (3 times the exposure to androgen deprivation therapy). The American Society for Therapeutic Radiology and Oncology biochemical failure definition was used. Results: Mean age was 69 years. Median follow-up time was 4.4 years (range, 1.5-14.5); 4 years for androgen deprivation therapy patients and 4.9 for radiation alone. There was no difference at 5 and 8 years in overall survival, cause-specific survival, or

Prenatal and adult androgen activities in alcohol dependence.

Science.gov (United States)

Lenz, B; Mühle, C; Braun, B; Weinland, C; Bouna-Pyrrou, P; Behrens, J; Kubis, S; Mikolaiczik, K; Muschler, M-R; Saigali, S; Sibach, M; Tanovska, P; Huber, S E; Hoppe, U; Eichler, A; Heinrich, H; Moll, G H; Engel, A; Goecke, T W; Beckmann, M W; Fasching, P A; Müller, C P; Kornhuber, J

2017-07-01

Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Further Evaluation of Androgen Therapy In Aplastic Anemia: With Special Reference to Correlation Between Response to Androgen and EEI

International Nuclear Information System (INIS)

Whang, Kee Suk

1967-01-01

Patients with aplastic anemia were treated with a combination of depo-testosterone cyclopentylpropionate (Upjohn) and dexamethasone. In 7 of 15 patients treated, there was response in which either a significant increase in hemoglobin concentration, a prolonged interval or a cessation of blood transfusion requirement developed during androgen therapy. Younger patients with cellular marrow appeared to be better responding to androgen. EEI (Effective Erythropoietic Index) formulated by Gardner and Nathan (1966) which was a helpful measurement as to whether patients with myelofibrosis would response to androgen, was evaluated in patients with aplastic anemia. It was concluded that EEI as well as ferrokinetics indices (Plasma- 59 Fe-disappearance rate, RBC 59 Fe net incorporation) did not significantly correlate with the degree of response to androgen in aplastic anemia.

Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation

NARCIS (Netherlands)

H.T. Brüggenwirth (Hennie); A.L.M. Boehmer (Annemie); S. Ramnarain; M.C. Verleun-Mooijman; D.P.E. Satijn (David); J. Trapman (Jan); J.A. Grootegoed (Anton); A.O. Brinkmann (Albert)

1997-01-01

textabstractIn the coding part and the intron-exon boundaries of the androgen-receptor gene of a patient with partial androgen insensitivity, no mutation was found. The androgen receptor of this patient displayed normal ligand-binding parameters and migrated as a

Further Evaluation of Androgen Therapy In Aplastic Anemia: With Special Reference to Correlation Between Response to Androgen and EEI

Energy Technology Data Exchange (ETDEWEB)

Whang, Kee Suk [Kyungpook National University School of Medicine, Deagu (Korea, Republic of)

1967-03-15

Patients with aplastic anemia were treated with a combination of depo-testosterone cyclopentylpropionate (Upjohn) and dexamethasone. In 7 of 15 patients treated, there was response in which either a significant increase in hemoglobin concentration, a prolonged interval or a cessation of blood transfusion requirement developed during androgen therapy. Younger patients with cellular marrow appeared to be better responding to androgen. EEI (Effective Erythropoietic Index) formulated by Gardner and Nathan (1966) which was a helpful measurement as to whether patients with myelofibrosis would response to androgen, was evaluated in patients with aplastic anemia. It was concluded that EEI as well as ferrokinetics indices (Plasma-{sup 59}Fe-disappearance rate, RBC {sup 59}Fe net incorporation) did not significantly correlate with the degree of response to androgen in aplastic anemia.

Evaluation of primary androgen deprivation therapy in prostate cancer patients using the J-CAPRA risk score

Science.gov (United States)

Akaza, Hideyuki; Hinotsu, Shiro; Usami, Michiyuki; Ogawa, Osamu; Kitamura, Tadaichi; Suzuki, Kazuhiro; Tsukamoto, Taiji; Naito, Seiji; Namiki, Mikio; Hirao, Yoshihiko; Murai, Masaru

2013-01-01

Purpose: To determine the influence of maximal androgen blockade (MAB) and non-MAB hormonal therapy with an luteinizing hormone releasing hormone (LHRH) analog on overall survival of prostate cancer patients in the Japan Study Group of Prostate Cancer (J-CaP) registry according to risk, as assessed using the novel J-CAPRA risk instrument. To undertake a multivariate analysis combining J-CAPRA risk score, type of hormonal therapy and comorbidities, in order to assess their impact on overall survival. Methods: The J-CaP database includes men in Japan diagnosed with any stage of prostate cancer between 2001 and 2003 and treated with primary androgen deprivation therapy (PADT), as monotherapy or in combination. A total of 26,272 men were enrolled and of these 19,265 were treated with PADT. This analysis was undertaken using the latest data set (30 April, 2010) including a total of 15,727 patients who received PADT and had follow-up data for periods ranging from 0 to 9.2 years. Results: MAB for prostate cancer patients with intermediate- or high-risk disease has a significant benefit in terms of overall survival compared with LHRH analog monotherapy or surgical castration alone. Better results may be achieved in older (≥75 years) patients. Patient comorbidities are an important factor in determining overall survival, notably in older patients, and should be considered when selecting therapy. Conclusions: Based on large-scale registry data, this report is the first to analyze the outcomes of MAB therapy in patients with prostate cancer at a wide range of disease stages. MAB therapy may provide significant survival benefits in intermediate- and high-risk patients. PMID:24223407

Androgen Receptor Signaling in Bladder Cancer

Science.gov (United States)

Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

2017-01-01

Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer. PMID:28241422

Androgen Receptor Signaling in Bladder Cancer

Directory of Open Access Journals (Sweden)

Peng Li

2017-02-01

Full Text Available Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer.

Sleep disturbance in men receiving androgen deprivation therapy for prostate cancer: The role of hot flashes and nocturia.

Science.gov (United States)

Gonzalez, Brian D; Small, Brent J; Cases, Mallory G; Williams, Noelle L; Fishman, Mayer N; Jacobsen, Paul B; Jim, Heather S L

2018-02-01

Patients with prostate cancer receiving androgen deprivation therapy (ADT) are at risk of sleep disturbance; however, to the authors' knowledge, the mechanisms by which ADT may affect sleep are not well understood. The current study compared objective and subjective sleep disturbance in ADT recipients and controls and examined whether sleep disturbance in ADT recipients is attributable to the influence of ADT on hot flashes and nocturia. Patients with prostate cancer were assessed before or within 1 month after the initiation of ADT as well as 6 months and 12 months later (78 patients). Patients with prostate cancer were treated with prostatectomy only (99 patients) and men with no history of cancer (108 men) were assessed at similar intervals. Participants self-reported their sleep disturbance (Insomnia Severity Index) and interference from hot flashes (Hot Flash Related Daily Interference Scale). One hundred participants also wore actigraphs for 3 days at the 6-month assessment to measure objective sleep disturbance and reported their nocturia frequency. ADT recipients reported worse sleep disturbance, higher rates of clinically significant sleep disturbance, and greater hot flash interference than controls (Ps≤.03). In cross-sectional analyses among those with actigraphy data, ADT recipients had greater objective sleep disturbance and more episodes of nocturia (Pshot flashes (Pshot flash interference. Future studies should examine behavioral and pharmacologic interventions to address these symptoms among ADT recipients. Cancer 2018;124:499-506. © 2017 American Cancer Society. © 2017 American Cancer Society.

Randomized, Double-Blinded, Placebo-Controlled, Trial of Risedronate for the Prevention of Bone Mineral Density Loss in Nonmetastatic Prostate Cancer Patients Receiving Radiation Therapy Plus Androgen Deprivation Therapy

Energy Technology Data Exchange (ETDEWEB)

Choo, Richard [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Lukka, Himu [Department of Radiation Oncology, Juravinski Cancer Center, McMaster University, Hamilton (Canada); Cheung, Patrick [Department of Radiation Oncology, Odette Cancer Centre, University of Toronto, Toronto (Canada); Corbett, Tom [Department of Radiation Oncology, Juravinski Cancer Center, McMaster University, Hamilton (Canada); Briones-Urbina, Rosario [Department of Medicine, Women' s College Hospital, University of Toronto, Toronto (Canada); Vieth, Reinhold [Departments of Nutritional Sciences and Laboratory Medicine and Pathology, Mount Sinai Hospital, University of Toronto, Toronto (Canada); Ehrlich, Lisa [Department of Radiology, Sunnybrook Health Sciences Center, University of Toronto (Canada); Kiss, Alex [Department of Health Policy, Management, and Evaluation, Sunnybrook Health Sciences Center, University of Toronto, Toronto (Canada); Danjoux, Cyril, E-mail: Cyril.danjoux@sunnybrook.ca [Department of Radiation Oncology, Odette Cancer Centre, University of Toronto, Toronto (Canada)

2013-04-01

Purpose: Androgen deprivation therapy (ADT) has been used as an adjuvant treatment to radiation therapy (RT) for the management of locally advanced prostate carcinoma. Long-term ADT decreases bone mineral density (BMD) and increases the risk of osteoporosis. The objective of this clinical trial was to evaluate the efficacy of risedronate for the prevention of BMD loss in nonmetastatic prostate cancer patients undergoing RT plus 2 to 3 years of ADT. Methods and Materials: A double-blinded, placebo-controlled, randomized trial was conducted for nonmetastatic prostate cancer patients receiving RT plus 2 to 3 years of ADT. All had T scores > −2.5 on dual energy x-ray absorptiometry at baseline. Patients were randomized 1:1 between risedronate and placebo for 2 years. The primary endpoints were the percent changes in the BMD of the lumbar spine at 1 and 2 years from baseline, measured by dual energy x-ray absorptiometry. Analyses of the changes in BMD and bone turnover biomarkers were carried out by comparing mean values of the intrapatient changes between the 2 arms, using standard t tests. Results: One hundred four patients were accrued between 2004 and 2007, with 52 in each arm. Mean age was 66.8 and 67.5 years for the placebo and risedronate, respectively. At 1 and 2 years, mean (±SE) BMD of the lumbar spine decreased by 5.77% ± 4.66% and 13.55% ± 6.33%, respectively, in the placebo, compared with 0.12% ± 1.29% at 1 year (P=.2485) and 0.85% ± 1.56% (P=.0583) at 2 years in the risedronate. The placebo had a significant increase in serum bone turnover biomarkers compared with the risedronate. Conclusions: Weekly oral risedronate prevented BMD loss at 2 years and resulted in significant suppression of bone turnover biomarkers for 24 months for patients receiving RT plus 2 to 3 years of ADT.

Randomized, Double-Blinded, Placebo-Controlled, Trial of Risedronate for the Prevention of Bone Mineral Density Loss in Nonmetastatic Prostate Cancer Patients Receiving Radiation Therapy Plus Androgen Deprivation Therapy

International Nuclear Information System (INIS)

Choo, Richard; Lukka, Himu; Cheung, Patrick; Corbett, Tom; Briones-Urbina, Rosario; Vieth, Reinhold; Ehrlich, Lisa; Kiss, Alex; Danjoux, Cyril

2013-01-01

Purpose: Androgen deprivation therapy (ADT) has been used as an adjuvant treatment to radiation therapy (RT) for the management of locally advanced prostate carcinoma. Long-term ADT decreases bone mineral density (BMD) and increases the risk of osteoporosis. The objective of this clinical trial was to evaluate the efficacy of risedronate for the prevention of BMD loss in nonmetastatic prostate cancer patients undergoing RT plus 2 to 3 years of ADT. Methods and Materials: A double-blinded, placebo-controlled, randomized trial was conducted for nonmetastatic prostate cancer patients receiving RT plus 2 to 3 years of ADT. All had T scores > −2.5 on dual energy x-ray absorptiometry at baseline. Patients were randomized 1:1 between risedronate and placebo for 2 years. The primary endpoints were the percent changes in the BMD of the lumbar spine at 1 and 2 years from baseline, measured by dual energy x-ray absorptiometry. Analyses of the changes in BMD and bone turnover biomarkers were carried out by comparing mean values of the intrapatient changes between the 2 arms, using standard t tests. Results: One hundred four patients were accrued between 2004 and 2007, with 52 in each arm. Mean age was 66.8 and 67.5 years for the placebo and risedronate, respectively. At 1 and 2 years, mean (±SE) BMD of the lumbar spine decreased by 5.77% ± 4.66% and 13.55% ± 6.33%, respectively, in the placebo, compared with 0.12% ± 1.29% at 1 year (P=.2485) and 0.85% ± 1.56% (P=.0583) at 2 years in the risedronate. The placebo had a significant increase in serum bone turnover biomarkers compared with the risedronate. Conclusions: Weekly oral risedronate prevented BMD loss at 2 years and resulted in significant suppression of bone turnover biomarkers for 24 months for patients receiving RT plus 2 to 3 years of ADT

The promotion on cell growth of androgen-dependent prostate cancer by antimony via mimicking androgen activity.

Science.gov (United States)

Zhang, Changwen; Li, Penghao; Wen, Yingwu; Feng, Guowei; Liu, Yu; Zhang, Yangyi; Xu, Yong; Zhang, Zhihong

2018-05-15

Antimony is a widely used heavier pnictogens in industry, and its toxicity has been a matter of concern. Although previous studies have suggested that antimony may have the function as either a tumor suppressor or an oncogene in several cancers, the molecular basis underlying antimony-mediated transformation is still unclear. In the current study, we attempt to elucidate the potential role of antimony in the development of prostate cancer. Our results showed that the concentration of antimony was much higher in serum of prostate cancer patients, and was closely associated with poor outcome of patients who underwent radical prostatectomy. Additionally, low dose of antimony could promote proliferation and invasion of androgen-dependent prostate cancer cell line LNCaP cells in vitro and in vivo. The mechanistic studies demonstrated that exposure to antimony triggered the phosphorylation of androgen receptor (AR), which transcriptionally regulates the expression of androgen-related targets, including PSA and NKX3.1. Overall, our results unearthed that antimony could promote tumor growth by mimicking androgen activity in androgen-dependent prostate cancer cells. Therefore, these findings expanded our understanding on the molecular mechanism of antimony in tumorigenesis and tumor progression of prostate cancer, and it appears to be an inspiring strategy to restrain prostate cancer by inhibiting antimony-induced androgen-like effects. Copyright © 2018 Elsevier B.V. All rights reserved.

Metabolic syndrome in patients with prostate cancer undergoing intermittent androgen-deprivation therapy.

Science.gov (United States)

Rezaei, Mohammadali Mohammadzadeh; Rezaei, Mohammadhadi Mohammadzadeh; Ghoreifi, Alireza; Kerigh, Behzad Feyzzadeh

2016-01-01

The presence of metabolic syndrome in men with prostate cancer (PCa) undergoing androgen-deprivation therapy (ADT), especially intermittent type, has not been completely evaluated. The aim of this study is to evaluate metabolic syndrome in men with PCa undergoing intermittent ADT. In this longitudinal study, we studied the prevalence of metabolic syndrome and its components in 190 patients who were undergoing intermittent ADT. The metabolic syndrome was defined according to the Adult Treatment Panel III criteria. All metabolic parameters, including lipid profile, blood glucose, blood pressures, and waist circumferences of the patients were measured six and 12 months after treatment. Mean age of the patients was 67.5 ± 6.74 years. The incidence of metabolic syndrome after six and 12 months was 6.8% and 14.7%, respectively. Analysis of various components of the metabolic syndrome revealed that patients had significantly higher overall prevalence of hyperglycemia, abdominal obesity, and hypertriglyceridemia in their six- and 12-month followups, but blood pressure has not been changed in the same period except for diastolic blood pressure after six months. Although there was an increased risk of metabolic syndrome in patients receiving intermittent ADT, it was lower than other studies that treated the same patients with continuous ADT. Also it seems that intermittent ADT has less metabolic complications than continuous ADT and could be used as a safe alternative in patients with advanced and metastatic PCa.

Upfront Androgen Deprivation Therapy With Salvage Radiation May Improve Biochemical Outcomes in Prostate Cancer Patients With Post-Prostatectomy Rising PSA

Energy Technology Data Exchange (ETDEWEB)

Jang, Joanne W. [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Hwang, Wei-Ting [Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Guzzo, Thomas J.; Wein, Alan J. [Department of Urology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Haas, Naomi B. [Department of Medical Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Both, Stefan [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Vapiwala, Neha, E-mail: vapiwala@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States)

2012-08-01

Purpose: The addition of androgen deprivation therapy (ADT) to definitive external beam radiation therapy (RT) improves outcomes in higher-risk prostate cancer patients. However, the benefit of ADT with salvage RT in post-prostatectomy patients is not clearly established. Our study compares biochemical outcomes in post-prostatectomy patients who received salvage RT with or without concurrent ADT. Methods and Materials: Of nearly 2,000 post-prostatectomy patients, we reviewed the medical records of 191 patients who received salvage RT at University of Pennsylvania between 1987 and 2007. Follow-up data were obtained by chart review and electronic polling of the institutional laboratory database and Social Security Death Index. Biochemical failure after salvage RT was defined as a prostate-specific antigen of 2.0 ng/mL above the post-RT nadir or the initiation of ADT after completion of salvage RT. Results: One hundred twenty-nine patients received salvage RT alone, and 62 patients received combined ADT and salvage RT. Median follow-up was 5.4 years. Patients who received combined ADT and salvage RT were younger, had higher pathologic Gleason scores, and higher rates of seminal vesicle invasion, lymph node involvement, and pelvic nodal irradiation compared with patients who received salvage RT alone. Patients who received combined therapy had improved biochemical progression-free survival (bPFS) compared with patients who received RT alone (p = 0.048). For patients with pathologic Gleason scores {<=}7, combined RT and ADT resulted in significantly improved bPFS compared to RT alone (p = 0.013). Conclusions: These results suggest that initiating ADT during salvage RT in the post-prostatectomy setting may improve bPFS compared with salvage RT alone. However, prospective randomized data are necessary to definitively determine whether hormonal manipulation should be used with salvage RT. Furthermore, the optimal nature and duration of ADT and the patient subgroups in

Complete androgen blockade safely allows for delay of cytotoxic chemotherapy in castration refractory prostate cancer

Directory of Open Access Journals (Sweden)

Rafael A. Kaliks

2010-06-01

Full Text Available PURPOSE: Complete androgen blockade (CAB does not prolong overall survival (OS in patients with castration refractory prostate cancer (CRPC. Although there is variable clinical benefit with second-line hormone manipulation, we do not know which patients might benefit the most. OBJECTIVES: To identify clinical predictors of benefit of complete androgen blockade. MATERIALS AND METHODS: We reviewed the records for 54 patients who received treatment with CAB in the setting of disease progression despite castration. We evaluated progression-free survival (PFS and OS according to PSA at diagnosis, Gleason scores, age, testosterone level, and duration of prior disease control during castration in first line treatment. RESULTS: Among 54 patients who received CAB, the median PFS was 9 months (CI 4.3-13.7 and OS was 36 months (CI 24-48. We did not find an effect of PSA at diagnosis (p = 0.32, Gleason score (p = 0.91, age (p = 0.69 or disease control during castration (p = 0.87 on PFS or OS. Thirty-four patients subsequently received chemotherapy, with a mean OS of 21 months (CI 16.4-25.5, median not reached. CONCLUSION: Age, Gleason score, PSA at diagnosis and length of disease control with castration did not affect PFS or OS. In the absence of predictors of benefit, CAB should still be considered in CRPC.

Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer.

Science.gov (United States)

Milowsky, Matthew I; Nanus, David M; Kostakoglu, Lale; Vallabhajosula, Shankar; Goldsmith, Stanley J; Bander, Neil H

2004-07-01

To determine the maximum-tolerated dose (MTD), toxicity, human antihuman antibody (HAHA) response, pharmacokinetics, organ dosimetry, targeting, and preliminary efficacy of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 ((90)Y-J591) in patients with androgen-independent prostate cancer (PC). Patients with androgen-independent PC and evidence of disease progression received indium-111-J591 for pharmacokinetic and biodistribution determinations followed 1 week later by (90)Y-J591 at five dose levels: 5, 10, 15, 17.5, and 20 mCi/m(2). Patients were eligible for up to three re-treatments if platelet and neutrophil recovery was satisfactory. Twenty-nine patients with androgen-independent PC received (90)Y-J591, four of whom were re-treated. Dose limiting toxicity (DLT) was seen at 20 mCi/m(2), with two patients experiencing thrombocytopenia with non-life-threatening bleeding episodes requiring platelet transfusions. The 17.5-mCi/m(2) dose level was determined to be the MTD. No re-treated patients experienced DLT. Nonhematologic toxicity was not dose limiting. Targeting of known sites of bone and soft tissue metastases was seen in the majority of patients. No HAHA response was seen. Antitumor activity was seen, with two patients experiencing 85% and 70% declines in prostate-specific antigen (PSA) levels lasting 8 and 8.6 months, respectively, before returning to baseline. Both patients had objective measurable disease responses. An additional six patients (21%) experienced PSA stabilization. The recommended dose for (90)Y-J591 is 17.5 mCi/m(2). Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation of (90)Y-J591 in the treatment of patients with PC.

Monotherapy of androgen deprivation therapy versus radical prostatectomy among veterans with localized prostate cancer: comparative effectiveness analysis of retrospective cohorts

Directory of Open Access Journals (Sweden)

Liu J

2012-05-01

Full Text Available Jinan Liu1,2, Lizheng Shi1,2,3, Oliver Sartor31Tulane University, School of Public Health and Tropical Medicine, 2Southeast Louisiana Veterans Health Care System, Tulane University, 3School of Medicine and Tulane Cancer Center, New Orleans, LA, USABackground: This retrospective cohort study aimed to examine the comparative effectiveness of monotherapy of primary androgen deprivation therapy or radical prostatectomy.Methods: Male patients with localized prostate cancer (T1-T2, N0, M0 were identified in the Veterans Affairs Veterans Integrated Service Network 16 data warehouse (January 2003 to June 2006, with one-year baseline and at least three-year follow-up data (until June 2009. Patients were required to be 18–75 years old and without other recorded cancer history. The initiation of primary androgen deprivation therapy or monotherapy of radical prostatectomy within six months after the first diagnosis of prostate cancer was used as the index date. Primary androgen deprivation therapy patients were matched to the radical prostatectomy patients via propensity score, which was predicted from a logistic regression of treatment selection (primary androgen deprivation therapy versus radical prostatectomy on age, race, marital status, insurance type, cancer stage, Charlson comorbidity index, and alcohol and tobacco use. The overall survival from initiation of index treatment was then analyzed using the Kaplan–Meier and Cox proportional hazards model.Results: The two cohorts were well matched at baseline (all P > 0.05. During a median follow-up of 4.3 years, the cumulative incidence of death was 13 (10.57% among 123 primary androgen deprivation therapy patients and four (3.25% among 123 radical prostatectomy patients (P < 0.05. The overall three-year survival rate was 92.68% for primary androgen deprivation therapy and 98.37% for radical prostatectomy (P < 0.05. Patients who received primary androgen deprivation therapy had almost three times as

Three novel and two known androgen receptor gene mutations ...

Indian Academy of Sciences (India)

gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients. J. Genet. ... signal and a C-terminal. Keywords. androgen insensitivity syndrome; androgen receptor; truncation mutation; N-terminal domain; XY sex reversal. .... and an increased risk of gonadal tumour. Mutations in SRY.

Androgen deficiency in male patients diagnosed with ANCA-associated vasculitis: a cause of fatigue and reduced health-related quality of life?

Science.gov (United States)

Tuin, Janneke; Sanders, Jan-Stephan F; Buhl, Birgit M; van Beek, André P; Stegeman, Coen A

2013-01-01

Low testosterone levels in men are associated with fatigue, limited physical performance and reduced health-related quality of life (HRQOL); however, this relationship has never been assessed in patients with anti-neutrophil cytoplasmic antibodies (ANCA) -associated vasculitides (AAV). The aim of this study was to assess the prevalence of androgen deficiency and to investigate the role of testosterone in fatigue, limited physical condition and reduced HRQOL in men with AAV. Male patients with AAV in remission were included in this study. Fatigue and HRQOL were assessed by the multi-dimensional fatigue inventory (MFI)-20 and RAND-36 questionnaires. Seventy male patients with a mean age of 59 years (SD 12) were included. Scores of almost all subscales of both questionnaires were significantly worse in patients compared to controls. Mean total testosterone and free testosterone levels were 13.8 nmol/L (SD 5.6) and 256 pmol/L (SD 102), respectively. Androgen deficiency (defined according to Endocrine Society Clinical Practice Guidelines) was present in 47% of patients. Scores in the subscales of general health perception, physical functioning and reduced activity were significantly worse in patients with androgen deficiency compared to patients with normal androgen levels. Testosterone and age were predictors for the RAND-36 physical component summary in multiple linear regression analysis. Testosterone, age, vasculitis damage index (VDI) and C-reactive protein (CRP) were associated with the MFI-20 subscale of general fatigue. This study showed that androgen deficiency was present in a substantial number of patients with AAV. Testosterone was one of the predictors for physical functioning and fatigue. Testosterone may play a role in fatigue, reduced physical performance and HRQOL in male patients with AAV.

The comparison of free androgen index and serum free testosterone levels in women with hirsutism or polycystic ovary syndrome

Directory of Open Access Journals (Sweden)

M. Metin Yıldırımkaya

2011-06-01

Full Text Available In many laboratories free testosterone can not be measured, so that free androgen index is suggested instead. The aim of this study was to compare free androgen index and serum free testosterone levels measured by radioimmunoassay in women with hirsutism or polycystic ovary syndrome.Materials and methods: Totally 94 women referred to the polyclinics of Ankara Numune Hospital were retrospectively included. Three patient groups were composed; 55 of hirsutism, 20 of polycystic ovary syndrome and 19 of both hirsutism and polycystic ovary syndrome. Total testosterone and sex hormone binding globuline levels were measured by chemiluminescence method and free testosterone levels were measured by radioimmunoassay. Free androgen index was calculated from total testosterone and sex hormone binding globuline.Results: There was a significant positive correlation between free testosterone and free androgen index in patients with hirsutism, in patients with polycystic ovary syndrome, in patients with hirsutism and polycystic ovary syndrome, and in total patient group [r(hirsutism=0,597, r(PCOS=0,617, r(hirsutism and PCOS=0,779, r(total patient group=0,649, P<0,01].Receiver operating characteristics curves were drawn to assess the diagnostic power of parameters for all patient groups [For hirsutism (n=55 auROC (FT=0,431 auROC (FAI=0,485] [For PCOS (n=20 auROC (FT=0,431 auROC (FAI=0,359] [For hirsutism and PCOS (n=19 auROC (FT=0,676 auROC (FAI=0,669]. In our study, free testosterone and free androgen index were found useful to diagnose ‘hirsutism and polycystic ovary syndrome’ but not others.Conclusion: Free androgen index can be used instead of free testosterone in hirsutism and polycystic ovary syndrome for diagnosis. J Clin Exp Invest 2011;2(2:152-6

Survival benefit associated with adjuvant androgen deprivation therapy combined with radiotherapy for high- and low-risk patients with nonmetastatic prostate cancer

International Nuclear Information System (INIS)

Zeliadt, Steven B.; Potosky, Arnold L.; Penson, David F.; Etzioni, Ruth

2006-01-01

Background: The use of adjuvant androgen deprivation therapy (ADT) combined with radiotherapy has become common in low-risk patients, although clinical trials have focused primarily on high-risk patients. This study examines the effectiveness of adjuvant ADT combined with radiotherapy for a wide range of patients treated in the 1990s. Methods and Materials: Prostate cancer survival was examined in a population based cohort of 31,643 patients aged 65 to 85 years who were diagnosed with nonmetastatic prostate cancer and treated with external beam radiotherapy and/or brachytherapy. Instrumental variable analysis methods were used to control for selection bias. Results: Patients with stage T3/T4 disease who received adjuvant ADT experienced improved 5-year and 8-year survival. No survival advantage was observed for men with T1/T2 disease during this interval. Conclusion: High-risk patients who receive primary radiotherapy have benefited from adjuvant ADT, whereas low-risk patients with disease confined to the prostate have not yet benefited from adjuvant therapy within the first 8 years after treatment. These findings are consistent with practice guidelines, which recommend adjuvant ADT for patients with high-risk disease

Partial androgen insensitivity syndrome due to somatic mosaicism of the androgen receptor.

Science.gov (United States)

Batista, Rafael Loch; Rodrigues, Andresa De Santi; Machado, Aline Zamboni; Nishi, Mirian Yumie; Cunha, Flávia Siqueira; Silva, Rosana Barbosa; Costa, Elaine M F; Mendonca, Berenice B; Domenice, Sorahia

2018-01-26

Androgen insensitivity syndrome (AIS) is the most frequent etiology of 46,XY disorders of sex development (DSDs), and it is an X-linked disorder caused by mutations in the androgen receptor (AR) gene. AIS patients present a broad phenotypic spectrum and individuals with a partial phenotype present with different degrees of undervirilized external genitalia. There are more than 500 different AR gene allelic variants reported to be linked to AIS, but the presence of somatic mosaicisms has been rarely identified. In the presence of a wild-type AR gene, a significant degree of spontaneous virilization at puberty can be observed, and it could influence the gender assignment, genetic counseling and the clinical and psychological management of these patients and the psychosexual outcomes of these patients are not known. In this study, we report two patients with AR allelic variants in heterozygous (c.382G>T and c.1769-1G>C) causing a partial AIS (PAIS) phenotype. The first patient was raised as female and she had undergone a gonadectomy at puberty. In both patients there was congruency between gender of rearing and gender identity and gender role. Somatic mosaicism is rare in AIS and nonsense AR variant allelic can cause partial AIS phenotype in this situation. Despite the risk of virilization and prenatal androgen exposure, the gender identity and gender role was concordant with sex of rearing in both cases. A better testosterone response can be expected in male individuals and this should be considered in the clinical management.

Baldness, benign prostate hyperplasia, prostate cancer and androgen levels.

Science.gov (United States)

Faydaci, Gökhan; Bilal, Eryildirim; Necmettin, Penpegül; Fatih, Tarhan; Asuman, Orçun; Uğur, Kuyumcuoğlu

2008-12-01

We evaluated the pattern of baldness and serum androgen levels in patients with benign prostate hyperplasia (BPH) and prostate cancer. BPH, prostate cancer and androgenic alopecia (AA) were somehow androgen dependent and affect large population of elderly men. A total of 152 patients, 108 patients with BPH and 44 patients with prostate cancer were included in the study. We measured serum total, free and bioavailable testosterone, FSH, LH, prolactin, estradiol, albumin and SHBG levels. Baldness classification was based on Norwood's classification and we categorised baldness as vertex and frontal baldness. The frequency of AA in BPH and prostate cancer groups were not different. We looked for some correlation between the two groups with respect to AA and hormone levels. We did not find any correlation between AA and total testosterone, free testosterone, bioavailable testosterone or SHBG levels in both groups. This prospective study with selected small group of patients showed that there is no difference of male pattern baldness in BPH and prostate cancer patients and also there is no correlation between pattern of baldness and serum androgen levels.

Clinical evaluation of internal iliac artery anticancer drug infusion for the treatment of androgen-independent prostate cancer

International Nuclear Information System (INIS)

Cao Ye; Wang Jin; Nie Yong; Chen Hua; Huang Xinjie

2008-01-01

Objective: To evaluate the clinical efficacy of bilateral internal iliac artery chemotherapy infusion for the treatment of androgen-independent prostate cancer (ALPC). Methods: Thirty eight eases of confirmed AIPC were randomly divided into treatment group and control group. The patients in treatment group (23 cases) were treated with androgen deprivation therapy and regular internal iliac artery chemotherapy, while patients in control group (15 cases) were only received androgen deprivation therapy. The therapeutic efficacies of the two groups were compared and analyzed after completion of the treatment. Results: The clinical symptoms and maximum urine flow rates of' treatment group were improved rapidly 6 months later. After 2 years follow-up, the total efficacies of treatment group and control group were 65.2% and 26.7% respectively, showing a significant statistical difference (P<0.05). Conclusions: The treatment of AlPC with bilateral internal iliac artery chemotherapy is effective, providing melioration the quality of life and alleviation of the symptoms. (authors)

Androgen excess: Investigations and management.

Science.gov (United States)

Lizneva, Daria; Gavrilova-Jordan, Larisa; Walker, Walidah; Azziz, Ricardo

2016-11-01

Androgen excess (AE) is a key feature of polycystic ovary syndrome (PCOS) and results in, or contributes to, the clinical phenotype of these patients. Although AE will contribute to the ovulatory and menstrual dysfunction of these patients, the most recognizable sign of AE includes hirsutism, acne, and androgenic alopecia or female pattern hair loss (FPHL). Evaluation includes not only scoring facial and body terminal hair growth using the modified Ferriman-Gallwey method but also recording and possibly scoring acne and alopecia. Moreover, assessment of biochemical hyperandrogenism is necessary, particularly in patients with unclear or absent hirsutism, and will include assessing total and free testosterone (T), and possibly dehydroepiandrosterone sulfate (DHEAS) and androstenedione, although these latter contribute limitedly to the diagnosis. Assessment of T requires use of the highest quality assays available, generally radioimmunoassays with extraction and chromatography or mass spectrometry preceded by liquid or gas chromatography. Management of clinical hyperandrogenism involves primarily either androgen suppression, with a hormonal combination contraceptive, or androgen blockade, as with an androgen receptor blocker or a 5α-reductase inhibitor, or a combination of the two. Medical treatment should be combined with cosmetic treatment including topical eflornithine hydrochloride and short-term (shaving, chemical depilation, plucking, threading, waxing, and bleaching) and long-term (electrolysis, laser therapy, and intense pulse light therapy) cosmetic treatments. Generally, acne responds to therapy relatively rapidly, whereas hirsutism is slower to respond, with improvements observed as early as 3 months, but routinely only after 6 or 8 months of therapy. Finally, FPHL is the slowest to respond to therapy, if it will at all, and it may take 12 to 18 months of therapy for an observable response. Copyright © 2016. Published by Elsevier Ltd.

A pilot study of exercise in men with prostate cancer receiving androgen deprivation therapy

International Nuclear Information System (INIS)

Lee, C Ellen; Leslie, William D; Lau, YK James

2012-01-01

Androgen deprivation therapy (ADT) is the mainstay therapy for men with prostate cancer. However, there are musculoskeletal side effects from ADT that increase the risk for osteoporosis and fracture, and can compromise the quality of life of these individuals. The objectives of this study are to determine the efficacy of a home-based walking exercise program in promoting bone health, physical function and quality of life in men with prostate cancer receiving ADT. A 12-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Sixty men with prostate cancer who will be starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 12-month home-based walking exercise program, while the Control Group will receive standard medical advice from the attending physician. A number of outcome measures will be used to assess bone health, physical function, and health-related quality of life. At baseline and 12 months, bone health will be assessed using dual-energy X-ray absorptiometry. At baseline and every 3 months up to 12 months, physical function will be evaluated using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, Activities-specific Balance Confidence Scale, Short Physical Performance Battery, and Six-Minute Walk Test; and health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy Prostate Module and the Medical Outcomes Study 12-item Short Form Health Survey Version 2. A mixed multiple analysis of variance will be used to analyze the data. Musculoskeletal health management remains a challenge in men with prostate cancer receiving ADT. This study addresses this issue by designing a simple and accessible home-based walking exercise program that will potentially have significant impact on reducing the risk of fracture, promoting physical

In Vitro Androgen Bioassays as a Detection Method for Designer Androgens

Directory of Open Access Journals (Sweden)

Alison K. Heather

2013-02-01

Full Text Available Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping.

The clinical and molecular spectrum of androgen insensitivity syndromes

Energy Technology Data Exchange (ETDEWEB)

Hiort, O.; Sinnecker, G.H.G.; Holterhus, P.M.; Nitsche, E.M.; Kruse, K. [Medical Univ. of Luebeck (Germany)

1996-05-03

Androgen insensitivity syndromes (AIS) are due to end-organ resistance to androgenic steroids in males leading to defective virilization of the external genitalia. The phenotype encompasses a wide array of genital ambiguity and may range from completely female to undervirilized but unequivocally male with infertility. This disorder is caused by mutations of the androgen receptor and is an X-linked recessive trait. We have studied 47 patients with AIS and have characterized the underlying molecular abnormality in the androgen receptor gene. Twenty patients had complete AIS and twenty-seven had partial AIS. Of the latter, 11 were of predominantly female phenotypic appearance and gender was assigned accordingly, while 16 were raised as males. Within the group of complete AIS, two patients had gross deletions within the gene, one had a small deletion, and one had an insertion. In the other patients with complete AIS, as well as all individuals with partial AIS, single nucleotide substitutions within the coding region were detected, each leading to an amino acid alteration. Seven codons were involved in more than one mutation in different cases. In addition, in one patient with spinal and bulbar muscular atrophy, an elongation of a glutamine-repeat was characterized. We conclude that mutations in the androgen receptor gene may be present throughout the whole coding region. However, our study provides evidence that several mutational hot spots exist. 18 refs., 2 figs.

Effects of androgen on immunohistochemical localization of androgen receptor and Connexin 43 in mouse ovary.

Science.gov (United States)

Yang, Mei; Li, Jianhua; An, Yulin; Zhang, Shuiwen

2015-10-01

Androgens have essential roles in the regulation of follicular development and female fertility. Androgen excess is the leading defect in polycystic ovary syndrome (PCOS) patients and involved in the ovarian dysfunction. The aim of this study was to elucidate the regarding regulatory role of androgen in the follicular development of female mouse. Immunohistochemical staining and Western blot analyses were performed to detect androgen receptor (AR) and Connexin 43 (Cx43) expression in ovaries from both control and testosterone-treated group mice. In this study, localizations of AR and Cx43 were dramatically altered in testosterone-treated mouse ovaries. In addition, AR expression was significantly increased, whereas Cx43 expression was markedly decreased after testosterone treatment. Alterations of AR and Cx43 expression by testosterone with concomitant reduction of MII oocytes. Overall, these results suggest the involvement of androgen in the regulation of AR and Cx43 localizations in mouse ovary. Alterations of AR and Cx43 expression by testosterone may affect normal folliculogenesis. Together these findings will enable us to begin understanding the important roles of AR and Cx43 actions in the regulation of follicular development, as well as providing insights into the role of AR and Cx43 actions in the androgen-associated reproductive diseases such as PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Androgen Receptor Expression in Thai Breast Cancer Patients

Directory of Open Access Journals (Sweden)

Suthat Chottanapund

2016-09-01

Full Text Available The aim of this study was to investigate prevalence and related factors of androgen receptor (AR expression in Thai breast cancer patients. A descriptive study was done in 95 patients, who were admitted to Charoenkrung Pracharak Hospital, Bangkok (2011–2013. Statistical relationships were examined between AR protein expression, tumor status, and patient characteristics. Compared with those from Western countries, ethnic Thai patients were younger at age of diagnosis and had a higher proliferative index (high Ki-67 expression, which indicates unfavorable prognosis. In addition, 91% of the Thai breast tumors that were positive for any of the following receptors, estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor 2 (HER2 also expressed the AR protein, while in triple negative breast tumors only 33% were AR positive. ER and PR expression was positively related with AR expression, while AR expression was inversely correlated to Ki-67 expression. AR status was strongly correlated with ER and PR status in Thai patients. There is an inverse relationship between Ki-67 and AR, which suggests that AR may be a prognostic factor for breast cancer.

External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

International Nuclear Information System (INIS)

Cho, Eunpi; Mostaghel, Elahe A.; Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A.; Kurland, Brenda F.; Marck, Brett T.; Matsumoto, Alvin M.; Dalkin, Bruce L.; Montgomery, R. Bruce

2015-01-01

Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

Energy Technology Data Exchange (ETDEWEB)

Cho, Eunpi [University of Washington School of Medicine, Seattle, Washington (United States); Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Mostaghel, Elahe A. [Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A. [University of Washington School of Medicine, Seattle, Washington (United States); Kurland, Brenda F. [University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Marck, Brett T. [Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Matsumoto, Alvin M. [University of Washington School of Medicine, Seattle, Washington (United States); Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Dalkin, Bruce L. [University of Washington School of Medicine, Seattle, Washington (United States); Montgomery, R. Bruce, E-mail: rbmontgo@uw.edu [University of Washington School of Medicine, Seattle, Washington (United States)

2015-06-01

Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

Selective androgen receptor modulators: in pursuit of tissue-selective androgens.

Science.gov (United States)

Omwancha, Josephat; Brown, Terry R

2006-10-01

The androgen receptor mediates the androgenic and anabolic activity of the endogenous steroids testosterone and 5alpha-dihydrotestosterone. Current knowledge of the androgen receptor protein structure, and the molecular mechanisms surrounding the binding properties and activities of agonists and antagonists has led to the design and development of novel nonsteroidal ligands with selected tissue-specific androgen receptor agonist and antagonist activities. The activity of these compounds, termed selective androgen receptor modulators (SARMs), is directed toward the maintenance or enhancement of anabolic effects on bone and muscle with minimal androgenic effects on prostate growth. SARMs are of potential therapeutic value in the treatment of male hypogonadism, osteoporosis, frailty and muscle wasting, burn injury and would healing, anemia, mood and depression, benign prostatic hyperplasia and prostate cancer.

Antiandrogens act as selective androgen receptor modulators at the proteome level in prostate cancer cells.

Science.gov (United States)

Brooke, Greg N; Gamble, Simon C; Hough, Michael A; Begum, Shajna; Dart, D Alwyn; Odontiadis, Michael; Powell, Sue M; Fioretti, Flavia M; Bryan, Rosie A; Waxman, Jonathan; Wait, Robin; Bevan, Charlotte L

2015-05-01

Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic

Androgens in women with anorexia nervosa and normal-weight women with hypothalamic amenorrhea.

Science.gov (United States)

Miller, K K; Lawson, E A; Mathur, V; Wexler, T L; Meenaghan, E; Misra, M; Herzog, D B; Klibanski, A

2007-04-01

Anorexia nervosa and normal-weight hypothalamic amenorrhea are characterized by hypogonadism and hypercortisolemia. However, it is not known whether these endocrine abnormalities result in reductions in adrenal and/ or ovarian androgens or androgen precursors in such women, nor is it known whether relative androgen deficiency contributes to abnormalities in bone density and body composition in this population. Our objective was to determine whether endogenous androgen and dehydroepiandrosterone sulfate (DHEAS) levels: 1) are reduced in women with anorexia nervosa and normal-weight hypothalamic amenorrhea, 2) are reduced further by oral contraceptives in women with anorexia nervosa, and 3) are predictors of weight, body composition, or bone density in such women. We conducted a cross-sectional study at a general clinical research center. A total of 217 women were studied: 137 women with anorexia nervosa not receiving oral contraceptives, 32 women with anorexia nervosa receiving oral contraceptives, 21 normal-weight women with hypothalamic amenorrhea, and 27 healthy eumenorrheic controls. Testosterone, free testosterone, DHEAS, bone density, fat-free mass, and fat mass were assessed. Endogenous total and free testosterone, but not DHEAS, were lower in women with anorexia nervosa than in controls. More marked reductions in both free testosterone and DHEAS were observed in women with anorexia nervosa receiving oral contraceptives. In contrast, normal-weight women with hypothalamic amenorrhea had normal androgen and DHEAS levels. Lower free testosterone, total testosterone, and DHEAS levels predicted lower bone density at most skeletal sites measured, and free testosterone was positively associated with fat-free mass. Androgen levels are low, appear to be even further reduced by oral contraceptive use, and are predictors of bone density and fat-free mass in women with anorexia nervosa. Interventional studies are needed to confirm these findings and determine whether

Computerized cognitive training in prostate cancer patients on androgen deprivation therapy: a pilot study.

Science.gov (United States)

Wu, Lisa M; Amidi, Ali; Tanenbaum, Molly L; Winkel, Gary; Gordon, Wayne A; Hall, Simon J; Bovbjerg, Katrin; Diefenbach, Michael A

2018-06-01

Prostate cancer patients who have undergone androgen deprivation therapy (ADT) may experience cognitive impairment, yet there is an unmet need for nonpharmacological interventions to address cognitive impairment in this population. This study examines the feasibility, acceptability, and preliminary efficacy of a home-based computerized cognitive training (CCT) program to treat cancer-related cognitive impairment. Sixty men who had received ≥ 3 months of ADT were screened for at least mild cognitive or neurobehavioral impairment and randomized to 8 weeks of CCT or usual care. Follow-up assessments occurred immediately post-intervention or equivalent (T2) and 8 weeks later (T3). The acceptability of CCT was also assessed. Feasibility:A priori feasibility thresholds were partially met (i.e., randomization rate > 50%, retention rate > 70% excluding CCT drop-outs, but cognitive functioning, neurobehavioral functioning, nor quality of life. This study provides tentative support for the feasibility and acceptability of CCT to treat mild cognitive impairment in ADT patients. CCT had a beneficial effect on reaction time, but temporarily suppressed memory. CCT's benefits may be limited to a narrow area of functioning. Larger-scale studies are needed.

Muscle Dysfunction in Androgen Deprivation: Role of Ryanodine Receptor

Science.gov (United States)

2016-11-01

reversible pharmacological treatment is a key therapeutic goal in prostate cancer patients. This life prolonging treatment is accompanied by the adverse... reversible pharmacological treatment, is a key therapeutic goal of androgen deprivation therapies (ADT) used in patients with androgen-dependent...gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. Aug 2000;85(8):2839

Androgenic alopecia; the risk–benefit ratio of Finasteride

Directory of Open Access Journals (Sweden)

David L. Rowland

2018-04-01

Full Text Available Finasteride is currently approved and largely used as a therapeutic option for androgenetic alopecia. Apparently a safe drug and effective at the onset, several concerns appeared over time regarding the frequency and magnitude of finasteride adverse effects, which in some cases seem to be even irreversible. This paper presents administration of finasteride in androgenic alopecia from two distinct perspectives. On one hand, androgenic alopecia is a condition that affects especially the self-image and esteem, aspects that are subjective, namely changeable and thus relative. On the other hand, this condition presents a multifactorial etiology, androgens being only in part involved. In addition, androgens have their own physiological roles within the body, so that any androgenic suppression should be carefully advised. Yet, adverse effects induced by Finasteride are only in part documented and treatable. Finally, alternative therapeutic approaches (like topical finasteride become available, so that the oral administration of Finasteride for androgenic alopecia should be in our opinion reevaluated. As a conclusion, a very detailed and informed discussion should take place with such patients accepting to start a therapy with finasteride for androgenic alopecia.

Role of androgen-mediated enhancement of erythropoiesis in the increased body iron stores of patients with polycystic ovary syndrome.

Science.gov (United States)

Escobar-Morreale, Héctor F; Luque-Ramírez, Manuel

2011-04-01

To determine whether androgen excess contributes to the increased body iron stores of polycystic ovary syndrome (PCOS) by stimulating erythropoietic activity, by measuring serum soluble transferrin receptor (sTfR) concentrations and its ratio to ferritin levels in patients with PCOS, as surrogate markers of erythropoietic activity and of the appropriateness of cellular iron demands for the total body iron contents, respectively. Case-control study. Academic hospital. One hundred-four patients with PCOS and 100 controls without androgen excess. Blood sampling and oral glucose tolerance test. Serum sTfR and ferritin concentrations, as well as indexes of androgen excess, inflammation, obesity, and insulin and glucose metabolism. Serum ferritin levels increased in women presenting with PCOS, obesity, and/or abnormal glucose tolerance, but these disorders did not influence sTfR concentrations. The sTfR/ferritin ratio decreased with obesity and abnormal glucose tolerance, and its logarithm correlated inversely with body mass index, free T, and C-reactive protein levels and directly with the insulin sensitivity and disposition indexes. A stepwise multiple regression analysis indicated that the changes in the insulin sensitivity index explained 7% of the variability of the logarithm of sTfR/ferritin ratio. Increased serum ferritin levels in patients with PCOS are associated with a reduction in insulin sensitivity but do not result from a putative enhancement of erythropoiesis by androgen excess. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Dissecting the roles of the androgen receptor in prostate cancer from molecular perspectives.

Science.gov (United States)

Hu, Jieping; Wang, Gongxian; Sun, Ting

2017-05-01

Androgen receptor plays a pivotal role in prostate cancer progression, and androgen deprivation therapy to intercept androgen receptor signal pathway is an indispensable treatment for most advanced prostate cancer patients to delay cancer progression. However, the emerging of castration-resistant prostate cancer reminds us the alteration of androgen receptor, which includes androgen receptor mutation, the formation of androgen receptor variants, and androgen receptor distribution in cancer cells. In this review, we introduce the process of androgen receptor and also its variants' formation, translocation, and function alteration by protein modification or interaction with other pathways. We dissect the roles of androgen receptor in prostate cancer from molecular perspective to provide clues for battling prostate cancer, especially castration-resistant prostate cancer.

The Relationship between Androgenic Alopecia and Prostate Cancer

Directory of Open Access Journals (Sweden)

Ghasem Rahmatpour Rokni

2016-07-01

Full Text Available Prostate cancer (PC and Androgenic Alopecia (AGA i are both common diseases in elder men. It seems that androgen plays a crucial role in the growth and development of prostate cancer. Therefore, the current study intended to investigate the relationship between androgenic alopecia and prostate cancer. The present study is a case-control study conducted on 75 patients with prostate cancer (case group referring to Imam Khomeini Hospital in Sari, Iran. The case group was compared with the control group (75 healthy individuals. The intended questionnaire of the study included information such as the age, sex, duration of disease, stage of disease, level of PSA, time diagnosis and time of interview for all the participants. The results of interview and clinical examination along with the patient’s information all were filled in the questionnaire and were statistically analyzed by SPSS after data collection. The mean age of PC group and healthy group was respectively 69.08 ± 8.97 and 68 .45 ± 10.16 years. The average level of PSA was 10.86 ± 11.7 and 2.66 ± 2.7 ng/ml in PC and healthy group in turn. The average duration of cancer was 12.63 ± 9.19 months in PC group. Furthermore, about 6.7% of cancer patients were in stage I, 48% were stage II, 29.3% were in stage III and 16% were in stage IV of prostate cancer. Besides, the number of cancer patients who had both frontal and vertex alopecia (baldness altogether exceeded healthy individuals (P=0.002. According to the results of the present study, there was a significant relationship between prostate cancer and androgenic alopecia which might have been caused by the effect of androgens on both diseases. Consequently, androgenic alopecia can be considered as one of the risk factors associated with prostate cancer.

Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Ragnum, Harald Bull [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Røe, Kathrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Holm, Ruth; Vlatkovic, Ljiljana [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Nesland, Jahn Marthin [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Aarnes, Eva-Katrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Ree, Anne Hansen [Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Flatmark, Kjersti [Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Department of Gastrointestinal Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Seierstad, Therese [Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Faculty of Health Sciences, Buskerud University College, Drammen (Norway); Lilleby, Wolfgang [Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Lyng, Heidi, E-mail: heidi.lyng@rr-research.no [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway)

2013-11-15

Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

International Nuclear Information System (INIS)

Ragnum, Harald Bull; Røe, Kathrine; Holm, Ruth; Vlatkovic, Ljiljana; Nesland, Jahn Marthin; Aarnes, Eva-Katrine; Ree, Anne Hansen; Flatmark, Kjersti; Seierstad, Therese; Lilleby, Wolfgang; Lyng, Heidi

2013-01-01

Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

Pretreatment Serum Testosterone and Androgen Deprivation: Effect on Disease Recurrence and Overall Survival in Prostate Cancer Patients Treated With Brachytherapy

International Nuclear Information System (INIS)

Taira, Al V.; Merrick, Gregory S.; Galbreath, Robert W.; Butler, Wayne M.; Wallner, Kent E.; Allen, Zachariah A.; Lief, Jonathan H.; Adamovich, Edward

2009-01-01

Purpose: Low testosterone has been implicated as a possible adverse prognostic factor in patients with newly diagnosed prostate cancer. We evaluated the impact of pretreatment serum testosterone on survival after prostate brachytherapy. Methods and Materials: From October 2001 to November 2004, 619 patients underwent brachytherapy and 546 had a pretreatment serum testosterone level measured. Pretreatment serum testosterone levels were assigned by the following criteria: below-normal (n = 105), low normal (n = 246), mid normal (n = 132), high normal (n = 50), and above normal (n = 13). Median follow-up was 5.2 years. Cause of death was determined for each deceased patient. Results: Six-year biochemical progression-free survival (bPFS), cause-specific survival (CSS), and overall survival (OS) were 97.7%, 99.8%, and 89.2%. When comparing patients with low or low normal testosterone with those with average or higher testosterone, there was no significant difference in bPFS (97.6% vs. 98.4%; p = 0.72), CSS (99.8% vs. 100%; p = 0.72), or OS (88.9% vs. 90.8%; p = 0.73). Among patients with average and higher pretreatment testosterone, there was no significant difference in outcomes when comparing patients who did and did not receive androgen deprivation therapy (ADT). For patients with low or low normal testosterone levels, there was no significant difference in bPFS or CSS when comparing patients who did and did not receive ADT. However, there was a trend toward lower OS in patients with baseline lower testosterone levels who also received ADT (83.9% vs. 91.3%, p = 0.075). Conclusions: Low pretreatment testosterone levels alone did not affect disease recurrence or OS. Patients with baseline low testosterone who also were treated with ADT had a trend toward decreased OS.

Establishing the cut off values of androgen markers in the assessment of polycystic ovarian syndrome.

Science.gov (United States)

Nadaraja, R N D; Sthaneshwar, P; Razali, N

2018-04-01

Hyperandrogenism remains as one of the key features in Polycystic Ovarian Syndrome (PCOS) and can be assessed clinically or determined by biochemical assays. Hirsutism is the most common clinical manifestation of hyperandrogenism. The clinical assessment is subjected to wide variability due to poor interobserver agreement and multiple population factors such as ethnic variation, cosmetic procedures and genetic trait. The difficulty in resolving the androgen excess biochemically is due to a lack of consensus as to which serum androgen should be measured for the diagnosis of PCOS. The aim of the study was to compare and establish the diagnostic cut off value for different androgen biomarker for the diagnosis of PCOS. A total of 312 patients classified to PCOS (n = 164) and non PCOS (n = 148) cohorts were selected from the Laboratory Information System (LIS) based on serum total testosterone (TT) and sex hormone binding globulin (SHBG) from the period of 1st April 2015 to 31st March 2016. PCOS was diagnosed based on Rotterdam criteria. Clinical hyperandrogenism and ultrasound polycystic ovarian morphology were obtained from the clinical records. The other relevant biochemical results such as serum luteinizing hormone (LH), follicle stimulating hormone (FSH) and albumin were also obtained from LIS. Free androgen index (FAI), calculated free testosterone (cFT) and calculated bioavailable testosterone (cBT) were calculated for these patients. Receiver Operating Characteristic (ROC) curve analysis were performed for serum TT, SHBG, FAI, cFT, cBT and LH: FSH ratio to determine the best marker to diagnose PCOS. All the androgen parameters (except SHBG) were significantly higher in PCOS patients than in control (pandrogen indices (FAI, cFT and cBT) showed good correlation with each other. Furthermore, cFT, FAI and calculated BT were shown to be more specific with higher positive likelihood ratio than measured androgen markers. Based on our study, the calculated testosterone

Maintaining intimacy for prostate cancer patients on androgen deprivation therapy.

Science.gov (United States)

Wassersug, Richard J

2016-03-01

Androgen deprivation therapy (ADT) causes erectile dysfunction and increases patients' emotionality while diminishing their sexual interest. ADT has been linked to erosion of spousal bonds; however, this is not an invariant outcome. Understanding the factors that lead to these various outcomes may help couples deal with ADT. A subset of couples report that they became closer as a result of the patients going on ADT. Recent data suggest that what helps couples most is preemptive awareness of ADT's side-effects and congruence in how patients and their partners understand and accept the psychosexual impact of ADT. Sex therapy for prostate cancer patients divides along gendered lines, with distinctly 'male' (recovery of erections) and 'female' (promoting sexual practices that are not erection dependent) approaches. Unfortunately, neither is very effective for couples when the patient is on ADT. Options beyond the standard gendered framework, such as use of an external penile prosthesis, may be worth offering to ADT patients trying to find a 'new normal' that is sexually rewarding for them. Intimacy is sharing something with someone that one shares with no one else. Exploring novel sexual practices can help couples stay intimate, even when the patient is on ADT.

Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis.

Science.gov (United States)

Kumagai, Jinpei; Hofland, Johannes; Erkens-Schulze, Sigrun; Dits, Natasja F J; Steenbergen, Jacobie; Jenster, Guido; Homma, Yukio; de Jong, Frank H; van Weerden, Wytske M

2013-11-01

Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown. The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. © 2013 Wiley Periodicals, Inc.

Anti-androgenic activity of absorption-enhanced 3, 3’-diindolylmethane in prostatectomy patients

OpenAIRE

Hwang, Clara; Sethi, Seema; Heilbrun, Lance K; Gupta, Nilesh S; Chitale, Dhananjay A; Sakr, Wael A; Menon, Mani; Peabody, James O; Smith, Daryn W; Sarkar, Fazlul H; Heath, Elisabeth I

2016-01-01

Consumption of cruciferous vegetables is associated with a decreased risk of developing prostate cancer. Antineoplastic effects of cruciferous vegetables are attributable to bioactive indoles, most prominently, 3, 3’-diindolylmethane (DIM). In addition to effects on proliferation and apoptosis, DIM acts as an antiandrogen in prostate cancer cell lines. This study characterized the effects of prostatic DIM on the androgen receptor (AR) in patients with prostate cancer. Men with localized prost...

The relationship of adrenal androgen level and insulin resistance in polycystic ovary syndrome patients

International Nuclear Information System (INIS)

Tan Qingling; Zhang Hui; Chen Biling

2011-01-01

Objective: To investigate the relationship between adrenal androgen level and insulin resistance in polycystic ovary syndrome (PCOS) patients. Methods: Twenty-two healthy women and 85 PCOS patients were underwent adrenocorticptropic hormone (ACTH) stimulation test, and 85 PCOS patients were divided into high response-polycystic ovary syndrome (HR-PCOS) group and normal response-polycystic ovary syndrome (NR-PCOS) group. The ratio of serum luteinizing hormone to follicle stimulating hormone (LH/FSH), estradiol (E 2 ), testosterone (T) and progestin (P) were tested by radioimmunoassay method. 17-hydroxy-progesterone (17-OHP), dehydroepiandros-teronesulfate (DHEAS) and androsterone (AD) was tested at 0 and 60 min after an ACTH stimulation test. Body mass index (BMI), waist-to-hip-circumference radio (WHR) and homeostasis modes of assessment for insulin resistence index (HOMA-IR) were also measured. Results: There were 20 cases that 17-OHP levels were higher than normal (HR-PCOS), the other 65 cases were NR-PCOS group. MBI and WHR(MBI: χ 2 =13.874, 14.512, WHR: χ 2 =12.607, 15.153, P all 2 =4.801, 5.326, P all>0.05). HR-PCOS group and NR-PCOS group were significantly higher than the control group for LH/FSH and estradiol (LH/FSH: χ 2 =18.226, 16.327, E2: χ 2 =17.334, 19.261, P all 2 =12.274, P 2 =20.314, 18.492, P all 2 =18.063, 19.214, DHEAS: χ 2 =17.358, 19.355, P all 2 =4.109, 4.362, P all>0.05). AD of HR-PCOS group and NR-PCOS group were higher than control group before and after the ACTH stimulation test (χ 2 =14.062, 16.549, P all 2 =5.541, P>0.05) between the two PCOS groups. Serum cortisol was no difference between HR-PCOS, NR-PCOS and control groups before and after stimulation test. HOMA-IR of HR-PCOS group and NR-PCOS group were higher than control group (χ 2 =19.263, 21.482, P all 2 =13.582, P<0.05). Conclusions: There have significantly higher basal and ACTH-stimulated level of adrenal androgen hyperresponsiveness in PCOS patients. Adrenal androgen

Androgen deprivation therapy (castration therapy and pedophilia: What’s new

Directory of Open Access Journals (Sweden)

Mauro Silvani

2015-09-01

Full Text Available Andrology is a constantly evolving discipline, embracing social problems like pedophilia and its pharmacological treatment. With regard to chemical castration, the andrologist may perform an important role as part of a team of specialists. At present, no knowledge is available regarding hormonal, chromosomal or genetic alterations involved in pedophilia. International legislation primarily aims to defend childhood, but does not provide for compulsory treatment. We reviewed international literature that, at present, only comprises a few reports on research concerning androgen deprivation. Most of these refer to the use of leuprolide acetate, rather than medroxyprogesterone and cyproterone acetate, which present a larger number of side effects. Current opinions on chemical castration for pedophilia are discordant. Some surveys confirm that therapy reduces sexual thoughts and fantasies, especially in recidivism. On the other hand, some authors report that chemical castration does not modify the pedophile’s personality. In our opinion, once existing legislation has changed, andrologists could play a significant role in the selection of patients to receive androgen deprivation therapy, due in part to their knowledge about its action and side effects.

Quality indicators for prostate radiotherapy: are patients disadvantaged by receiving treatment in a 'generalist' centre?

Science.gov (United States)

Freeman, Amanda R; Roos, Daniel E; Kim, Laurence

2015-04-01

The purpose of this retrospective review was to evaluate concordance with evidence-based quality indicator guidelines for prostate cancer patients treated radically in a 'generalist' (as distinct from 'sub-specialist') centre. We were concerned that the quality of treatment may be lower in a generalist centre. If so, the findings could have relevance for many radiotherapy departments that treat prostate cancer. Two hundred fifteen consecutive patients received external beam radiotherapy (EBRT) and/or brachytherapy between 1.10.11 and 30.9.12. Treatment was deemed to be in line with evidence-based guidelines if the dose was: (i) 73.8-81 Gy at 1.8-2.0 Gy/fraction for EBRT alone (eviQ guidelines); (ii) 40-50 Gy (EBRT) for EBRT plus high-dose rate (HDR) brachytherapy boost (National Comprehensive Cancer Network (NCCN) guidelines); and (iii) 145 Gy for low dose rate (LDR) I-125 monotherapy (NCCN). Additionally, EBRT beam energy should be ≥6 MV using three-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT), and high-risk patients should receive neo-adjuvant androgen-deprivation therapy (ADT) (eviQ/NCCN). Treatment of pelvic nodes was also assessed. One hundred four high-risk, 84 intermediate-risk and 27 low-risk patients (NCCN criteria) were managed by eight of nine radiation oncologists. Concordance with guideline doses was confirmed in: (i) 125 of 136 patients (92%) treated with EBRT alone; (ii) 32 of 34 patients (94%) treated with EBRT + HDR BRT boost; and (iii) 45 of 45 patients (100%) treated with LDR BRT alone. All EBRT patients were treated with ≥6 MV beams using 3D-CRT (78%) or IMRT (22%). 84%, 21% and 0% of high-risk, intermediate-risk and low-risk patients received ADT, respectively. Overall treatment modality choice (including ADT use and duration where assessable) was concordant with guidelines for 176/207 (85%) of patients. The vast majority of patients were treated concordant with evidence-based guidelines suggesting that

Influence of radiotherapy on node-positive prostate cancer treated with androgen ablation

Energy Technology Data Exchange (ETDEWEB)

Sands, M Elizabeth; Pollack, Alan; Zagars, Gunar K

1995-01-01

Purpose: Patients with node-positive prostate cancer that is regionally localized (T1-4, N1-3, M0) have a relatively poor prognosis when a single-treatment modality such as radical surgery, definitive radiotherapy, or androgen ablation is used. While promising results using radical surgery and androgen ablation have been reported, there are no data to support an analogous approach using local radiotherapy and androgen ablation. In this retrospective review, the outcome after local radiotherapy and early androgen ablation (XRT/HORM) was compared to early androgen ablation alone (HORM). Methods and Materials: Between 1984 and 1992 there were 181 patients treated with HORM and 27 patients treated with XRT/HORM at the University of Texas M. D. Anderson Cancer Center. The nodal status of all patients was established pathologically by lymph node dissection, which was terminated after frozen section confirmation of involvement. In the majority of cases androgen ablation was by orchiectomy. The median dose to the prostate in XRT/HORM group was 66 Gy. The median follow-up was 45 months; 49 months for the HORM group and 25 months for the XRT/HORM group. Results: The distribution of prognostic factors between the HORM and XRT/HORM groups was similar, with the exception of tumor grade. There was a significantly larger proportion of high grade tumors in the HORM group. In terms of actuarial disease outcome, at 4 years the results of patients in the HORM group were significantly worse, including a rising prostate specific antigen (PSA) of 53%, any disease progression of 32%, a rising PSA or disease progression of 55%, and local progression of 22%. None of the patients in the XRT/HORM group failed biochemically or clinically. To determine the impact of grade on these findings, the analyses were repeated, using only those with grade 2 tumors. A similar pattern was evidenced with significantly worse actuarial outcome at 4 years for the HORM group using the endpoints of a rising PSA

The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

International Nuclear Information System (INIS)

Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V.

2010-01-01

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

Molecular basis of androgen insensitivity

NARCIS (Netherlands)

Brinkmann, A.; Jenster, G.; Ris-Stalpers, C.; van der Korput, H.; Brüggenwirth, H.; Boehmer, A.; Trapman, J.

1996-01-01

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. In the X-linked androgen insensitivity syndrome, defects in the

Integrating diet and exercise into care of prostate cancer patients on androgen deprivation therapy

Directory of Open Access Journals (Sweden)

Moyad MA

2016-08-01

Full Text Available Mark A Moyad,1 Robert U Newton,2 Ulf W Tunn,3 Damian Gruca4 1Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA; 2Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia; 3Urological Clinic, Facharztzentrum Academic Hospital Sana Klinikum Offenbach, Offenbach/Main, 4Global Medical Affairs, AbbVie Deutschland, Ludwigshafen, Germany Abstract: Improved diagnosis and treatment regimens have resulted in greater longevity for men with prostate cancer. This has led to an increase in both androgen deprivation therapy (ADT use and duration of exposure, and therefore to its associated adverse effects, such as sexual dysfunction, osteoporosis, reduced muscle mass, increased fat mass, and increased incidence of cardiovascular disease and type 2 diabetes. Given that the adverse effects of ADT are systemic, often debilitating, and difficult to treat, efforts continue in the development of new strategies for long-term management of prostate cancer. The PubMed database was searched to select trials, reviews, and meta-analyses in English using such search terms as “prostate cancer” and “androgen deprivation therapy”, “cardiovascular risk”, “lean body mass”, “exercise”, and “diet”. The initial searches produced 379 articles with dates 2005 or more recent. Articles published after 2004 were favored. This review utilizes the latest data to provide a status update on the effects of exercise and diet on patients with prostate cancer, focusing on ADT-associated side effects, and it discusses the evidence for such interventions. Since the evidence of large-scale trials in patients with prostate cancer is missing, and an extrapolation of supporting data to all patient subgroups cannot be provided, individualized risk assessments remain necessary before the initiation of exercise and diet programs. Exercise, diet, and nutritional supplementation interventions have the potential to

GGC and StuI polymorphism on the androgen receptor gene in endometrial cancer patients

International Nuclear Information System (INIS)

Sasaki, Masahiro; Karube, Akihiro; Karube, Yuko; Watari, Michiko; Sakuragi, Noriaki; Fujimoto, Seiichiro; Dahiya, Rajvir

2005-01-01

Androgens have an anti-proliferative effect on endometrial cells. Human androgen receptor (AR) gene contains two polymorphic short tandem repeats of GGC and CAG, and a single-nucleotide polymorphism on exon 1 that is recognized by the restriction enzyme, StuI. Prior studies have shown that the lengths of the CAG repeat are inversely and linearly related to AR activity and associated with endometrial cancer. However, little is known about the GGC repeat and the StuI polymorphism of the AR gene. Thus, we investigated whether these AR polymorphisms are risk factors for endometrial cancer. To test this hypothesis, the genetic distributions of these polymorphisms were investigated in blood samples from endometrial cancer patients and healthy controls. The allelic and genotyping profiles were analyzed by polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (PCR-RFLP), and direct DNA sequencing, and analyzed statistically. The GGC repeat was significantly longer in endometrial cancer patients as compared to normal healthy controls. In general, an increased risk of endometrial cancer was found with increasing GGC repeat. The relative risk for the 17 GGC repeat was greater than 4, as compared to controls. However, the StuI polymorphism was not significantly different between patients and controls. The findings suggest that increased numbers of GGC repeat on the AR gene may be a risk factor for endometrial cancer

Association of mean platelet volume with androgens and insulin resistance in nonobese patients with polycystic ovary syndrome.

Science.gov (United States)

Dogan, Bercem Aycicek; Arduc, Ayse; Tuna, Mazhar Muslum; Karakılıc, Ersen; Dagdelen, Iffet; Tutuncu, Yasemin; Berker, Dilek; Guler, Serdar

2014-10-01

Mean platelet volume (MPV) is generally accepted as a new marker of cardiovascular disease risk in several studies. This study aimed to determine the association of MPV with androgen hormones and insulin resistance (IR) in nonobese patients with polycystic ovary syndrome (PCOS). A total of 136 patients with newly diagnosed reproductive-age PCOS (regarding the criteria of new PCOS phenotypes, based on the Rotterdam criteria) who were nonobese with the mean age of 25 years (25.39 ± 5.51) and mean body mass index (BMI) of 21 kg/m(2) (22.07 ± 2.13) were included. In addition, 59 healthy subjects with mean age of 26 years (22.07 ± 2.13) and mean BMI of 22 kg/m(2) (21.52 ± 3.84) were recruited as control. Total blood count (including MPV), total testosterone, free testosterone, dehydroepiandrosterone-sulfate (DHEAS), and androstenedione levels were recorded. IR was calculated from blood chemistry measurements of fasting insulin and glucose according to updated homeostasis model assessment. No differences were observed in mean MPV values between patients and control group (9.02 fL (8.5-10.1) and 8.9 fL (7.7-9.1), respectively; P = 0.777). MPV values were similar among nonobese patients with and without IR and control subjects (P > 0.05). We detected significantly lower values of MPV in patients with hyperandrogenemia in comparison to patients with normal androgen levels (8.7 and 9.5 fL, P = 0.012). There was a negative correlation between total testosterone, DHEAS, and MPV (P = 0.016, r = -0.229; and P = 0.006, r = -0.261, respectively). Multiple logistic regression analyses confirmed the independence of these associations. Our study revealed that nonobese women with and without PCOS have similar MPV values. While IR does not have any effect on MPV, elevated androgen levels are associated with a low MPV in nonobese patients with PCOS.

Prognostic factors in Chinese patients with prostate cancer receiving primary androgen deprivation therapy: validation of Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score and impacts of pre-existing obesity and diabetes mellitus.

Science.gov (United States)

Hu, Meng-Bo; Yang, Tian; Hu, Ji-Meng; Zhu, Wen-Hui; Jiang, Hao-Wen; Ding, Qiang

2018-06-01

Our aim was to determine the prognostic factors in Chinese patients with prostate cancer receiving primary androgen deprivation therapy (PADT), validate the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score, and investigate the impacts of pre-existing obesity and diabetes mellitus (DM). The study enrolled Chinese patients diagnosed with prostatic adenocarcinoma and treated with bilateral orchiectomy as PADT at Huashan Hospital, Fudan University (Shanghai, China), from January 2003 to December 2015. The overall survival (OS) and prognostic value of J-CAPRA score, pre-existing obesity, DM, and various clinicopathological variables were analyzed. Of the 435 patients enrolled, 174 (40.0%) deaths occurred during follow-up; 3- and 5-year OS were 74.0 and 58.9%, respectively. Multivariate analysis identified that higher Gleason score and metastasis were both correlated with worse OS and that higher J-CAPRA score was correlated with worse OS [hazard ratio (HR) 1.110, 95% confidence interval (CI) 1.035-1.190, P = 0.003). Different risk categories based on J-CAPRA score showed good stratification in OS (log-rank P = 0.015). In subgroup analysis, pre-existing obesity as a protective factor in younger patients (age ≤ 65, HR 0.271, 95% CI 0.075-0.980, P = 0.046) and pre-existing DM as a risk factor in older patients (> 75, HR 1.854, 95% CI 1.026-3.351, P = 0.041) for OS were recognized, and the prediction accuracy of J-CAPRA was elevated after incorporating pre-existing obesity and DM. The J-CAPRA score presented with good OS differentiation among Chinese patients under PADT. Younger patients (age ≤ 65) had better OS with pre-existing obesity, while older patients (age > 75) had worse OS with pre-existing DM.

Polycystic ovary syndrome patients with high BMI tend to have functional disorders of androgen excess: a prospective study.

Science.gov (United States)

Yuan, Chun; Liu, Xiaoqiang; Mao, Yundong; Diao, Feiyang; Cui, Yugui; Liu, Jiayin

2016-05-01

Biochemical or clinical changes of hyperandrogenism are important elements of polycystic ovary syndrome (PCOS). There is currently no consensus on the definition and diagnostic criteria of hyperandrogenism in PCOS. The aim of this study was to investigate the complex symptoms of hyperandrogenic disorders and the correlations between metabolism and hyperandrogenism in patients with PCOS from an outpatient reproductive medicine clinic in China. We conducted a case control study of 125 PCOS patients and 130 controls to evaluate differences in body mass index (BMI), total testosterone (TT), modified Ferriman-Gallwey hirsutism score, sex hormone binding globulin (SHBG), homeostasis model assessment-estimated insulin resistance (HOMA-IR) and free androgen index (FAI) between PCOS patients and controls and subgroups of PCOS. The prevalence of acne and hirsutism did not differ significantly between the hyperandrogenic and non-hyperandrogenic subgroup. Patients with signs of hyperandrogenism had significantly higher BMI (P PCOS patients. Our results suggest that PCOS patients with high BMI tend to have functional disorders of androgen excess; therefore, BMI may be a strong predictor of hyperandrogenism in PCOS. © 2016 the Journal of Biomedical Research. All rights reserved.

A Phase II Trial of Docetaxel with Rapid Androgen Cycling as a Treatment for Patients with Prostate Cancer

Science.gov (United States)

Rathkopf, Dana; Carducci, Michael A.; Morris, Michael J.; Slovin, Susan F.; Eisenberger, Mario A.; Pili, Roberto; Denmeade, Samuel R.; Kelsen, Moshe; Curley, Tracy; Priet, Regina; Collins, Connie; Fleisher, Martin; Heller, Glenn; Baker, Sharyn D.; Scher, Howard I.

2011-01-01

Purpose We evaluated rapid androgen cycling in combination with docetaxel for men with progressive non-castrate prostate cancers. Methods Non-castrate patients with ≤ 6 months of hormones were eligible. Cohort 1 (63 patients ) received 6 28-day cycles of docetaxel (75 mg/m2), leuprolide and 7 days of topical testosterone. Cohort 2 (39 patients) received 9 21-day cycles of docetaxel (70 mg/m2), leuprolide and 3 days of testosterone. The primary endpoint was the proportion of patients at 18 months who achieved non -castrate testosterone levels (>150 ng/dl) and an undetectable PSA (≤ 0.05, ≤0.5, or ≤2.0 ng/ml with prior prostatectomy, radiotherapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated. Results A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% vs. 0%). The 16% incidence of febrile neutropenia was higher than observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the non-castrate group. There was no alteration in CYP3A4 activity (P=0.87) or docetaxel clearance (P=0.88) between cycles. Conclusions The undetectable PSA endpoint allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles following a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with non-castrate vs castrate testosterone levels. PMID:18565882

Effect of propofol on androgen receptor activity in prostate cancer cells.

Science.gov (United States)

Tatsumi, Kenichiro; Hirotsu, Akiko; Daijo, Hiroki; Matsuyama, Tomonori; Terada, Naoki; Tanaka, Tomoharu

2017-08-15

Androgen receptor is a nuclear receptor and transcription factor activated by androgenic hormones. Androgen receptor activity plays a pivotal role in the development and progression of prostate cancer. Although accumulating evidence suggests that general anesthetics, including opioids, affect cancer cell growth and impact patient prognosis, the effect of those drugs on androgen receptor in prostate cancer is not clear. The purpose of this study was to investigate the effect of the general anesthetic propofol on androgen receptor activity in prostate cancer cells. An androgen-dependent human prostate cancer cell line (LNCaP) was stimulated with dihydrotestosterone (DHT) and exposed to propofol. The induction of androgen receptor target genes was investigated using real-time reverse transcription polymerase chain reaction, and androgen receptor protein levels and localization patterns were analyzed using immunoblotting and immunofluorescence assays. The effect of propofol on the proliferation of LNCaP cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Propofol significantly inhibited DHT-induced expression of androgen receptor target genes in a dose- and time-dependent manner, and immunoblotting and immunofluorescence assays indicated that propofol suppressed nuclear levels of androgen receptor proteins. Exposure to propofol for 24h suppressed the proliferation of LNCaP cells, whereas 4h of exposure did not exert significant effects. Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Risk of fracture in men with prostate cancer on androgen deprivation therapy: a population-based cohort study in New Zealand

International Nuclear Information System (INIS)

Wang, Alice; Obertová, Zuzana; Brown, Charis; Karunasinghe, Nishi; Bishop, Karen; Ferguson, Lynnette; Lawrenson, Ross

2015-01-01

Androgen deprivation therapy (ADT) administered as a prostate cancer treatment is known to exert multiple side effects including bone deterioration leading to bone fracture. The current analysis is to evaluate the burden of fracture risk in the New Zealand prostate cancer (PCa) population treated with ADT, and to understand the subsequent risk of mortality after a fracture. Using datasets created through linking records from the New Zealand Cancer Registry, National Minimal Dataset, Pharmaceutical Collection and Mortality Collection, we studied 25,544 men (aged ≥40 years) diagnosed with PCa between 2004 and 2012. ADT was categorised into the following groups: gonadotropin-releasing hormone (GnRH) agonists, anti-androgens, combined androgen blockade (GnRH agonists plus anti-androgens), bilateral orchiectomy, and bilateral orchiectomy plus pharmacologic ADT (anti-androgens and/or GnRH agonists). Among patients receiving ADT, 10.8 % had a fracture compared to 3.2 % of those not receiving ADT (p < 0.0001). After controlling for age and ethnicity, the use of ADT was associated with a significantly increased risk of any fracture (OR = 2.83; 95 % CI 2.52–3.17) and of hip fracture requiring hospitalisation (OR = 1.82; 95 % CI 1.44–2.30). Those who received combined androgen blockade (OR = 3.48; 95 % CI 3.07–3.96) and bilateral orchiectomy with pharmacologic ADT (OR = 4.32; 95 % CI 3.34–5.58) had the greatest risk of fracture. The fracture risk following different types of ADT was confounded by pathologic fractures and spinal cord compression (SCC). ADT recipients with fractures had a 1.83-fold (95 % CI 1.68–1.99) higher mortality risk than those without a fracture. However, after the exclusion of pathologic fractures and SCC, there was no increased risk of mortality. ADT was significantly associated with an increased risk of any fracture and hip fracture requiring hospitalisation. The excess risk was partly driven by pathologic fractures and SCC which are

Concept and viability of androgen annihilation for advanced prostate cancer.

Science.gov (United States)

Mohler, James L

2014-09-01

There remains no standard of care for patients with a rising prostate-specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single-institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen-sensitive cells survive to adapt to a low-androgen environment. Androgens may be "annihilated" simultaneously using a luteinizing hormone-releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α-reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand-binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy. © 2014 American Cancer Society.

Androgen deficiency in the aging male and chronic prostatitis: clinical and diagnostic comparative analysis

Directory of Open Access Journals (Sweden)

Spirin Р.V.

2013-03-01

Full Text Available The research goal is to study probability, period of development and characteristics of a clinical course of chronic prostatitis against the background of androgen deficiency in the aging male. Materials and methods: The Aging Male Symptoms (AMS rating scale has been applied for androgen deficiency evaluation and the International Prostate Symptom Score (IPSS — for chronic prostatitis evaluation. 57 men with chronic prostatitis in combination with androgen deficiency in the aging male have been examined. Results: It has been concluded that the development of chronic prostatitis against the background of androgen deficiency in the aging male occurs in a shorter time period and about 1.5 times more frequently compared to androgen deficiency in the aging male at the background of chronic prostatitis. The analysis of time periods between the onset of chronic prostatitis symptoms against the background of androgen deficiency in the aging male and androgen deficiency in the aging male symptoms against the background of chronic prostatitis showed that androgen deficiency in the aging male symptoms have been revealed 1-2 years earlier than the onset of chronic prostatitis. The development of androgen deficiency in the aging male against the background of chronic prostatitis has showed a backward tendency. Signs of chronic prostatitis have been more frequently occurred in a period of four-five years earlier the androgen deficiency in the aging male development. Conclusion: The risk of development of chronic prostatitis against the background of androgen deficiency in the aging male during the next two years is actually four times higher in comparison with the development of androgen deficiency in the aging male against the background of chronic prostatitis. According to the International Prostate Symptom Score (IPSS, patients with chronic prostatitis in combination with androgen deficiency in the aging male showed higher degree of severity than

Androgen Bioassay for the Detection of Nonlabeled Androgenic Compounds in Nutritional Supplements.

Science.gov (United States)

Cooper, Elliot R; McGrath, Kristine C Y; Li, XiaoHong; Heather, Alison K

2018-01-01

Both athletes and the general population use nutritional supplements. Athletes often turn to supplements hoping that consuming the supplement will help them be more competitive and healthy, while the general population hopes to improve body image or vitality. While many supplements contain ingredients that may have useful properties, there are supplements that are contaminated with compounds that are banned for use in sport or have been deliberately adulterated to fortify a supplement with an ingredient that will produce the advertised effect. In the present study, we have used yeast cell and mammalian cell androgen bioassays to characterize the androgenic bioactivity of 112 sports supplements available from the Australian market, either over the counter or via the Internet. All 112 products did not declare an androgen on the label as an included ingredient. Our findings show that six out of 112 supplements had strong androgenic bioactivity in the yeast cell bioassay, indicating products spiked or contaminated with androgens. The mammalian cell bioassay confirmed the strong androgenic bioactivity of five out of six positive supplements. Supplement 6 was metabolized to weaker androgenic bioactivity in the mammalian cells. Further to this, Supplement 6 was positive in a yeast cell progestin bioassay. Together, these findings highlight that nutritional supplements, taken without medical supervision, could expose or predispose users to the adverse consequences of androgen abuse. The findings reinforce the need to increase awareness of the dangers of nutritional supplements and highlight the challenges that clinicians face in the fast-growing market of nutritional supplements.

A polymorphism in a transporter of testosterone is a determinant of androgen independence in prostate cancer.

Science.gov (United States)

Sharifi, Nima; Hamada, Akinobu; Sissung, Tristan; Danesi, Romano; Venzon, David; Baum, Caitlin; Gulley, James L; Price, Douglas K; Dahut, William L; Figg, William D

2008-08-05

To determine if patients with advanced prostate cancer carrying a polymorphism that codes for a more active testosterone transporter have less durable responses to androgen-deprivation therapy (ADT) than patients not carrying this polymorphism. We previously determined that a polymorphism in SLCO1B3 affects testosterone transport and that those men who have at least one wild-type T allele at the 334 T > G polymorphism in this gene have a shorter survival. We hypothesized that the T allele which increases testosterone transport would be associated with a shorter interval from ADT to androgen independence. We examined the association between this SLCO1B3 polymorphism and time from ADT to androgen independence, ADT to prostate-specific antigen (PSA) nadir and PSA nadir to androgen independence in 68 Caucasian patients with advanced prostate cancer who were treated with ADT with metastatic disease (D2) or biochemical failure with no metastatic disease (D0). When examined separately, patients in the individual stages tended to have a shorter time to androgen independence with the T allele in the D0 (P = 0.11) and D2 (P = 0.18) groups. Combining these groups and stratifying by stage yielded a statistically significant shorter time to androgen independence with the T allele (P = 0.048). A polymorphism in a transporter that increases testosterone import is associated with a shorter time to androgen independence in patients with prostate cancer who are treated with ADT.

Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

Science.gov (United States)

Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

2008-07-01

Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.

Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied modifications in the steroidal structure.

Science.gov (United States)

Fragkaki, A G; Angelis, Y S; Koupparis, M; Tsantili-Kakoulidou, A; Kokotos, G; Georgakopoulos, C

2009-02-01

Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone introduced for therapeutic purposes providing enhanced anabolic potency with reduced androgenic effects. Androgens mediate their action through their binding to the androgen receptor (AR) which is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver and central nervous system. This paper reviews some of the wide spectrum of testosterone and synthetic AAS structure modifications related to the intended enhancement in anabolic activity. The structural features of steroids necessary for effective binding to the AR and those which contribute to the stipulation of the androgenic and anabolic activities are also presented.

The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

Energy Technology Data Exchange (ETDEWEB)

Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V., E-mail: lstewart@mmc.edu

2010-12-10

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

Development of a Nomogram Model Predicting Current Bone Scan Positivity in Patients Treated with Androgen-Deprivation Therapy for Prostate Cancer

Science.gov (United States)

Gotto, Geoffrey T.; Yu, Changhong; Bernstein, Melanie; Eastham, James A.; Kattan, Michael W.

2014-01-01

Purpose: To develop a nomogram predictive of current bone scan positivity in patients receiving androgen-deprivation therapy (ADT) for advanced prostate cancer; to augment clinical judgment and highlight patients in need of additional imaging investigations. Materials and methods: A retrospective chart review of bone scan records (conventional 99mTc-scintigraphy) of 1,293 patients who received ADT at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011. Multivariable logistic regression analysis was used to identify variables suitable for inclusion in the nomogram. The probability of current bone scan positivity was determined using these variables and the predictive accuracy of the nomogram was quantified by concordance index. Results: In total, 2,681 bone scan records were analyzed and 636 patients had a positive result. Overall, the median pre-scan prostate-specific antigen (PSA) level was 2.4 ng/ml; median PSA doubling time (PSADT) was 5.8 months. At the time of a positive scan, median PSA level was 8.2 ng/ml; 53% of patients had PSA <10 ng/ml; median PSADT was 4.0 months. Five variables were included in the nomogram: number of previous negative bone scans after initiating ADT, PSA level, Gleason grade sum, and history of radical prostatectomy and radiotherapy. A concordance index value of 0.721 was calculated for the nomogram. This was a retrospective study based on limited data in patients treated in a large cancer center who underwent conventional 99mTc bone scans, which themselves have inherent limitations. Conclusion: This is the first nomogram to predict current bone scan positivity in ADT-treated prostate cancer patients, providing high predictive accuracy. PMID:25386410

Development of a nomogram model predicting current bone scan positivity in patients treated with androgen-deprivation therapy for prostate cancer

Directory of Open Access Journals (Sweden)

Michael eKattan

2014-10-01

Full Text Available Purpose: To develop a nomogram predictive of current bone scan positivity in patients receiving androgen-deprivation therapy (ADT for advanced prostate cancer; to augment clinical judgment and highlight patients in need of additional imaging investigations.Materials and Methods: A retrospective chart review of bone scan records (conventional 99mTc-scintigraphy of 1,293 patients who received ADT at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011. Multivariable logistic regression analysis was used to identify variables suitable for inclusion in the nomogram. The probability of current bone scan positivity was determined using these variables and the predictive accuracy of the nomogram was quantified by concordance index.Results: In total, 2,681 bone scan records were analyzed and 636 patients had a positive result. Overall, the median pre-scan prostate-specific antigen (PSA level was 2.4 ng/ml; median PSA doubling time (PSADT was 5.8 months. At the time of a positive scan, median PSA level was 8.2 ng/ml; 53% of patients had PSA <10 ng/ml; median PSADT was 4.0 months. Five variables were included in the nomogram: number of previous negative bone scans after initiating ADT, PSA level, Gleason grade sum, and history of radical prostatectomy and radiotherapy. A concordance index value of 0.721 was calculated for the nomogram. This was a retrospective study based on limited data in patients treated in a large cancer centre who underwent conventional 99mTc bone scans, which themselves have inherent limitations. Conclusions: This is the first nomogram to predict current bone scan positivity in ADT-treated prostate cancer patients, providing high predictive accuracy.

Androgen receptor variant-7: an important predictive biomarker in castrate resistant prostate cancer

Directory of Open Access Journals (Sweden)

Oliver Sartor

2015-06-01

Full Text Available The recent manuscript in New England Journal of Medicine by Antonarakis et al. [1] has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 (AR-V7, in circulating tumor cells (CTCs from metastatic castrate-resistant prostate cancer (mCRPC patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen (PSA responses. Further, the median time to PSA progression after enzalutamide or abiraterone treatment was only 1.3-1.4 months in AR-V7-positive patients as compared to 5.3-6.1 months in AR-V7 negative patients. AR-V7 in CTCs was also associated with shorter survival.

Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy

DEFF Research Database (Denmark)

Hvid, Thine; Winding, Kamilla; Rinnov, Anders

2013-01-01

Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine me...... and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P...

Androgens and alopecia.

Science.gov (United States)

Kaufman, Keith D

2002-12-30

Androgens have profound effects on scalp and body hair in humans. Scalp hair grows constitutively in the absence of androgens, while body hair growth is dependent on the action of androgens. Androgenetic alopecia, referred to as male pattern hair loss (MPHL) in men and female pattern hair loss (FPHL) in women, is due to the progressive miniaturization of scalp hair. Observations in both eunuchs, who have low levels of testicular androgens, and males with genetic 5alpha-reductase (5alphaR) deficiency, who have low levels of dihydrotestosterone (DHT), implicate DHT as a key androgen in the pathogenesis of MPHL in men. The development of finasteride, a type 2-selective 5alphaR inhibitor, further advanced our understanding of the role of DHT in the pathophysiology of scalp alopecia. Controlled clinical trials with finasteride demonstrated improvements in scalp hair growth in treated men associated with reductions in scalp DHT content, and a trend towards reversal of scalp hair miniaturization was evident by histopathologic evaluation of scalp biopsies. In contrast to its beneficial effects in men, finasteride did not improve hair growth in postmenopausal women with FPHL. Histopathological evaluation of scalp biopsies confirmed that finasteride treatment produced no benefit on scalp hair in these women. These findings suggest that MPHL and FPHL are distinct clinical entities, with disparate pathophysiologies. Studies that elucidate the molecular mechanisms by which androgens regulate hair growth would provide greater understanding of these differences. Copyright 2002 Elsevier Science Ireland Ltd.

PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

International Nuclear Information System (INIS)

Zhang, Zheng; Jin, Bo; Jin, Yaqiong; Huang, Shengquan; Niu, Xiaohua; Mao, Zebin; Xin, Dianqi

2017-01-01

Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that the PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.

Neoadjuvant androgen deprivation and prostate gland shrinkage during conformal radiotherapy

International Nuclear Information System (INIS)

Sanguineti, Giuseppe; Marcenaro, Michela; Franzone, Paola; Foppiano, Franca; Vitale, Vito

2003-01-01

Purpose: The shrinking effect of 3-month neoadjuvant androgen deprivation (NAD) on preradiotherapy prostate gland volume is well documented. However, recently, it has been shown that the cancerous prostate gland keeps shrinking up to 12 months after NAD start. Thus, if such a reduction is not taken into account, a larger than planned portion of the surrounding normal tissues might shift in the high-dose region during conformal radiotherapy (3DCRT) course. The present study was undertaken to quantify this issue. Materials and Methods: Prostate gland volume reduction between planning CT (plCT) and the last week of 3DCRT (tmtCT) was prospectively assessed in 33 consecutive patients with localized prostate carcinoma. The median time interval between plCT and tmtCT was 2.5 months (2.1-2.7 months). A single observer was asked to draw on each slice prostate gland volume as appropriate. The observer was 'blind' to the timing of CT (plCT vs. tmtCT). In order to estimate intra-observer variability, prostate gland delineation was repeated twice for each data set. Mean prostate gland change, plCT and tmtCT cumulative dose volume histogram (DVH) calculations for the rectum were analyzed for each patient. Results were correlated to AD status and its duration before plCT. Means were compared by non-parametric rank tests. Results: Based on an internal protocol, 14 patients (42%) did not receive AD, while 19 patients (58%) had undergone neoadjuvant and concomitant AD. The median duration of AD before plCT ranged from 0.2 to 6 months (median: 2.9 months). Although individual data were highly variable, compared to plCT volume, mean prostate gland volume change at the end of 3DCRT was similar for patients receiving (-7.3%) or not (-7%) androgen deprivation (P=0.77). However, within the group of patients treated with hormones, patients starting AD within 3 months from plCT had a significantly larger reduction in prostate volume (-14.2%) than patients with longer NAD duration (-1.1%, P

Preferred treatment frequency in patients receiving androgen deprivation therapy for advanced prostate cancer

DEFF Research Database (Denmark)

Fode, Mikkel; Nielsen, Torben K; Al-Hamadani, Muhammad

2014-01-01

satisfaction and side-effects. Overall, 238 men receiving ADT for prostate cancer were presented with the questionnaire between September 2011 and May 2012. Descriptive statistics, the chi-squared test and multiple regression were used for analyses. RESULTS: In total, 176 questionnaires (74%) were available...

Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

International Nuclear Information System (INIS)

Zumsteg, Zachary S.; Spratt, Daniel E.; Pei, Xin; Yamada, Yoshiya; Kalikstein, Abraham; Kuk, Deborah; Zhang, Zhigang; Zelefsky, Michael J.

2013-01-01

Purpose: We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. Methods and Materials: The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. Results: The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Conclusions: Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy

Complete Androgen Insensitivity Syndrome: A Rare Case of Disorder of Sex Development

Directory of Open Access Journals (Sweden)

Alfonsa Pizzo

2013-01-01

Full Text Available Androgen Insensitivity Syndrome (AIS could be considered as a disease that causes resistance to androgens actions, influencing both the morphogenesis and differentiation of the body structures, and systems in which this hormone exerts its effects. It depends on an X-linked mutations in the Androgen Receptor (AR gene that express a variety of phenotypes ranging from male infertility to completely normal female external genitalia. The clinical phenotypes of AIS could vary and be classified into three categories, as complete (CAIS, partial (PAIS, and mild (MAIS forms, according to the severity of androgen resistance. We will describe a case of CAIS in a 16-year-old patient.

Tissue polypeptide-specific antigen (TPS) determinations before and during intermittent maximal androgen blockade in patients with metastatic prostatic carcinoma

NARCIS (Netherlands)

Kil, P. J. M.; Goldschmidt, H. M. J.; Wieggers, B. J. A.; Kariakine, O. B.; Studer, U. E.; Whelan, P.; Hetherington, J.; de Reijke, Th M.; Hoekstra, J. W.; Collette, L.

2003-01-01

To evaluate the prognostic significance of serially measured tissue polypeptide-specific antigen (TPS) levels in patients with metastatic prostatic carcinoma treated with intermittent maximal androgen blockade (MAB). To determine its value with respect to predicting response to treatment and time to

Investigation of patients with atypical or severe hyperandrogenaemia including androgen-secreting ovarian teratoma.

LENUS (Irish Health Repository)

Dennedy, Michael Conall

2012-02-01

Approximately 7% of women of reproductive age manifest polycystic ovary syndrome (PCOS) and <0.5% have other causes of hyperandrogenism including congenital adrenal hyperplasia (CAH), androgen-secreting tumour of an ovary or an adrenal gland, Cushing\\'s syndrome or hyperthecosis. The presence of features atypical of PCOS should prompt more extensive evaluation than that usually undertaken. Features atypical of PCOS include the onset of symptoms outside the decade of 15-25 years, rapid progression of symptoms, the development of virilization and a serum testosterone concentration in excess of twice the upper limit of the reference range. Ethnic background, family history and specific clinical findings, e.g. Cushingoid appearance, may inform a focused investigation. Otherwise, patients should have measurement of 17-hydroxyprogesterone (17-OHP) under basal conditions ideally in the early morning, and if abnormal, they should have measurement of 17-OHP one hour after the administration of synthetic ACTH, 250 microg i.v., to screen for CAH, which is present in approximately 2% of hyperandrogenic patients. The overnight cortisol suppression test employing 1 mg dexamethasone at midnight is a sensitive test for Cushing\\'s syndrome. Coronal tomographic (CT) scanning of the adrenals and transvaginal ultrasonography of the ovaries are the investigations of choice when screening for tumours in these organs. Less frequently required is catheterization and sampling from both adrenal and ovarian veins, which is a technically demanding procedure with potential complications which may provide definitive diagnostic information not available from other investigations. Illustrative case reports highlight some complexities in the investigation of hyperandrogenic patients presenting with features atypical of PCOS and include only the ninth case report of an androgen-secreting ovarian teratoma.

11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome.

Science.gov (United States)

O'Reilly, Michael W; Kempegowda, Punith; Jenkinson, Carl; Taylor, Angela E; Quanson, Jonathan L; Storbeck, Karl-Heinz; Arlt, Wiebke

2017-03-01

Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to androgen excess in women with PCOS. One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four-hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. Baseline demographic data, including body mass index, were recorded. As expected, serum concentrations of the classic androgens testosterone (P PCOS. Mirroring this, serum 11-oxygenated androgens 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11β-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in patients with PCOS compared with control subjects [53.0% (interquartile range, 48.7 to 60.3) vs 44.0% (interquartile range, 32.9 to 54.9); P PCOS had significantly increased 11-oxygenated androgens. Serum 11β-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance. We show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk.

Intratumoral androgen metabolism and actions in invasive lobular carcinoma of the breast.

Science.gov (United States)

Yoda, Tomomi; McNamara, Keely May; Miki, Yasuhiro; Takagi, Mayu; Rai, Yoshiaki; Ohi, Yasuyo; Sagara, Yasuaki; Tamaki, Kentaro; Hirakawa, Hisashi; Ishida, Takanori; Suzuki, Takashi; Ohuchi, Noriaki; Sasano, Hironobu

2014-11-01

Invasive lobular carcinoma (ILC) accounts for approximately 10% of all breast carcinomas and is characterized by higher levels of androgen receptor (AR) compared to invasive ductal carcinoma (IDC). Despite this potentially androgen-responsive environment, the combined importance of AR and androgen metabolism in non-neoplastic lobules and lobular carcinoma remains unknown. Therefore, in this study, we evaluated the status of pivotal androgen-producing enzymes 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) and 5α-reductase type 1 (5αRed1) in 178 cases of ILC and surrounding histologically non-neoplastic lobular tissue using immunohistochemistry. Androgen receptor prevalence was higher but androgenic enzymes lower in ILC than non-neoplastic lobules. In ILC cases the status of 5αRed1 and 17βHSD5 was inversely correlated with tumor size (P = 0.0053) and nuclear grade (P = 0.0290), and significantly associated with better overall survival of the patients (P = 0.0059). Based on these findings, we hypothesized that androgen signaling could act as a tumor suppressor. As previous studies suggested that androgens might partially act by increasing levels of the estrogen inactivating enzyme 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) in IDC tissues, this was reasonably considered a potential mechanism of androgen actions. Significantly positive correlation was detected between the status of androgenic enzymes and 17βHSD2 (P Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance

DEFF Research Database (Denmark)

Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun

2014-01-01

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conse......Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity...... is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved...... in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls...

Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism.

Science.gov (United States)

Carmina, E; Rosato, F; Jannì, A; Rizzo, M; Longo, R A

2006-01-01

We undertook this study to estimate the prevalence of the various androgen excess disorders using the new criteria suggested for the diagnosis of polycystic ovary syndrome (PCOS). The study was performed at two endocrine departments at the University of Palermo (Palermo, Italy). The records of all patients referred between 1980 and 2004 for evaluation of clinical hyperandrogenism were reevaluated. All past diagnoses were reviewed using the actual diagnostic criteria. To be included in this study, the records of the patients had to present the following available data: clinical evaluation of hyperandrogenism, body weight and height, testosterone (T), free T, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, progesterone, and pelvic sonography. A total of 1226 consecutive patients were seen during the study period, but only the scores of 950 patients satisfied all criteria and were reassessed for the diagnosis. The prevalence of androgen excess disorders was: PCOS, 72.1% (classic anovulatory patients, 56.6%; mild ovulatory patients, 15.5%), idiopathic hyperandrogenism, 15.8%; idiopathic hirsutism, 7.6%; 21-hydroxylase-deficient nonclassic adrenal hyperplasia, 4.3%; and androgen-secreting tumors, 0.2%. Compared with other androgen excess disorders, patients with PCOS had increased body weight whereas nonclassic adrenal hyperplasia patients were younger and more hirsute and had higher serum levels of T, free T, and 17-hydroxyprogesterone. Classic PCOS is the most common androgen excess disorder. However, mild androgen excess disorders (ovulatory PCOS and idiopathic hyperandrogenism) are also common and, in an endocrine setting, include about 30% of patients with clinical hyperandrogenism.

Androgens and polycystic ovary syndrome.

Science.gov (United States)

Nisenblat, Vicki; Norman, Robert J

2009-06-01

Polycystic ovary syndrome (PCOS) is a common complex endocrine genetic disorder, which involves overproduction of androgens, leading to heterogeneous range of symptoms and associated with increased metabolic and cardiovascular morbidity. This review focuses on androgen biosynthesis, use, metabolism in PCOS and clinical consequences of hyperandrogenism. Controversial definition of the disorder and different phenotypic subgroups present a challenge for clinical and basic research. Further investigation of different phenotypes highlights the fact that PCOS probably represents a group of disorders with different etiologies. Prenatal androgen exposure and adolescent studies suggest early in life androgen excess as initiating factor of PCOS, but insufficient evidence available to confirm this hypothesis. Various intracellular signaling pathways implicated in PCOS steroidogenesis and in androgen action have been studied, however, PCOS pathogenesis remains obscure. Growing evidence links androgens with pathophysiology of PCOS and metabolic derangements. Despite intensive investigation, etiology and underlying mechanisms of PCOS remain unclear, warranting further investigation. Better understanding of molecular and genetic basis might lead to invention of novel therapeutic approaches. Long-term interventional studies that lower androgen levels in women with hyperandrogenism might protect against metabolic and cardiovascular comorbidities are needed.

PROGNOSTIC VALUE OF THE BASELINE VALUES OF SERUM TESTOSTERONE AND FREE ANDROGEN INDEX IN PATIENTS WITH PROSTATE CANCER

Directory of Open Access Journals (Sweden)

M. E. Grigoryev

2012-01-01

Full Text Available The growing incidence of prostate cancer (PC and its variable nature are an important problem today. PC is distinguished by its latent ability in many cases, which makes its screening difficult.Prostate-specific antigen (PSA is one of the most common tumor markers of PC, which are used for mass male screening. However, the detection rate of PC in men with normal PSA values is also very high. This promotes an active search for new markers and predictors of PC.The effect of androgens on hormonal carcinogenesis in the prostate suggests that the analysis of serum testosterone concentrations and free androgen index may be made in patients with low PSA levels in the early diagnosis and prognosis of PC.

Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?

Science.gov (United States)

Corbould, A

2008-10-01

Hyperinsulinemia as a consequence of insulin resistance causes hyperandrogenemia in women. The objective was to review evidence for the converse situation, i.e. whether androgens adversely influence insulin action. Androgen excess could potentially contribute to the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS), metabolic syndrome/type 2 diabetes, and in obese peripubertal girls. An Entrez-PubMed search was conducted to identify studies addressing the relationship of androgens with metabolic syndrome/type 2 diabetes in women. Studies reporting outcomes of androgen administration, interventions to reduce androgen effects in hyperandrogenemic women, and basic studies investigating androgen effects on insulin target tissues were reviewed. Multiple studies showed associations between serum testosterone and insulin resistance or metabolic syndrome/type 2 diabetes risk in women, but their cross-sectional nature did not allow conclusions about causality. Androgen administration to healthy women was associated with development of insulin resistance. Intervention studies in women with hyperandrogenism were limited by small subject numbers and use of indirect methods for assessing insulin sensitivity. However, in three of the seven studies using euglycemic hyperinsulinemic clamps, reduction of androgen levels or blockade of androgen action improved insulin sensitivity. Testosterone administration to female rats caused skeletal muscle insulin resistance. Testosterone induced insulin resistance in adipocytes of women in vitro. In conclusion, the metabolic consequences of androgen excess in women have been under-researched. Studies of long-term interventions that lower androgen levels or block androgen effects in young women with hyperandrogenism are needed to determine whether these might protect against metabolic syndrome/type 2 diabetes in later life. Copyright (c) 2008 John Wiley & Sons, Ltd.

[Osteoporosis fracture in a male patient secondary to hypogonadism due to androgen deprivation treatment for prostate cancer].

Science.gov (United States)

Verdú Solans, J; Roig Grau, I; Almirall Banqué, C

2014-01-01

A 84 year-old patient, in therapy with androgen deprivation during the last 5 years due a prostate cancer, is presented with a osteoporotic fracture of the first lumbar vertebra. The pivotal role of the primary care physician, in the prevention of the osteoporosis secondary to the hypogonadism in these patients, is highlighted. Copyright © 2012 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

Androgen responsiveness of the new human endometrial cancer cell line MFE-296.

Science.gov (United States)

Hackenberg, R; Beck, S; Filmer, A; Hushmand Nia, A; Kunzmann, R; Koch, M; Slater, E P; Schulz, K D

1994-04-01

MFE-296 endometrial cancer cells express androgen receptors in vitro. These cells, which are tumorigenic in nude mice, are derived from a moderately differentiated human endometrial adenocarcinoma. They express vimentin and the cytokeratins 7, 8, 18, and 19. Karyotyping revealed near-tetraploidy for most of the cells. No marker chromosomes were observed. DNA analyses confirmed the genetic identity of the cell line and the patient from whom the cell line was derived. Proliferation of MFE-296 cells was inhibited by the progestin R5020 and the androgen dihydrotestosterone (DHT). The inhibition of proliferation by DHT was antagonized by the antiandrogen Casodex, demonstrating the involvement of the androgen receptor. Androgen binding was determined at 22,000 binding sites per cell using a whole-cell assay (KD = 0.05 nM) and 30 fmol/mg protein with the dextran charcoal method; 7 fmol/mg protein of progesterone receptors were found, whereas estrogen receptors were below 5 fmol/mg protein. The androgen receptor was functionally intact, as demonstrated by transfection experiments with a reporter-gene construct, containing an androgen-responsive element. In MFE-296 cells the content of the androgen receptor was up-regulated by its own ligand.

Implementation of High-Dose-Rate Brachytherapy and Androgen Deprivation in Patients With Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Lilleby, Wolfgang, E-mail: wolfgang.lilleby@ous-hf.no [Cancer Clinic, Oslo University Hospital, Norwegian Radiumhospital, Department of Radiotherapy and Oncology, Oslo (Norway); Tafjord, Gunnar; Raabe, Nils K. [Cancer Clinic, Oslo University Hospital, Norwegian Radiumhospital, Department of Radiotherapy and Oncology, Oslo (Norway)

2012-07-01

Purpose: To evaluate outcome (overall survival [OS], the actuarial 5-year cancer-specific survival [CSS], disease-free survival [DFS], biochemical failure-free survival [BFS]), complications and morbidity in patients treated with high-dose-rate brachytherapy (HDR-BT) boost and hormonal treatment with curative aims. Methods: Between 2004 and 2009, 275 prospectively followed pN0/N0M0 patients were included: 19 patients (7%) with T2, Gleason score 7 and prostate-specific antigen (PSA) <10 and 256 patients (93%) with T3 or Gleason score 8-10 or PSA >20 received multimodal treatment with conformal four-field radiotherapy (prostate/vesiculae 2 Gy Multiplication-Sign 25) combined with HDR-BT (iridium 192; prostate 10 Gy Multiplication-Sign 2) with long-term androgen deprivation therapy (ADT). Results: After a median observation time of 44.2 months (range, 10.4-90.5 months) 12 patients had relapsed clinically and/or biochemically and 10 patients were dead, of which 2 patients died from prostate cancer. Five-year estimates of BFS, CSS, DFS, and OS rates were 98.5%, 99.3%, 95.6%, and 96.3%, respectively. None of the patients with either Gleason score <8 or with intermediate risk profile had relapsed. The number of HDR-BT treatments was not related to outcome. Despite of age (median, 65.7 years; range, 45.7-77 years) and considerable pretreatment comorbidity in 39 of 275 patients, Genitourinary treatment-related morbidity was moderate with long-lasting Radiation Therapy Oncology Group Grade 2 voiding problems in 26 patients (9.5%) and occasionally mucous discharge in 20 patients (7%), none with Grade >2 for gastrointestinal at follow-up. Complications during implantations were related to pubic arch interference (4 patients) and lithotomy time, causing 2 patients to develop compartment syndrome. Conclusion: Despite still preliminary observations, our 5-year outcome estimates favor the implementation of high-dose-rate brachytherapy in high-risk patients combined with conformal

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

NARCIS (Netherlands)

L.J. Blok (Leen); G.T.G. Chang; M. Steenbeek-Slotboom (M.); W.M. van Weerden (Wytske); H.G. Swarts; J.J.H.H.M. de Pont (J. J H H M); G.J. van Steenbrugge (Gert Jan); A.O. Brinkmann (Albert)

1999-01-01

textabstractThe β1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of

Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

Science.gov (United States)

Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

2016-07-22

It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. Copyright © 2016 Elsevier Inc. All rights reserved.

Androgen deficiency and dry eye syndrome in the aging male.

Science.gov (United States)

Azcarate, Patrick M; Venincasa, Vincent D; Feuer, William; Stanczyk, Frank; Schally, Andrew V; Galor, Anat

2014-07-03

To evaluate the relationship between androgen levels and subjective and objective measures of dry eye syndrome (DES). A total of 263 male patients from the Miami Veterans Affairs Medical Center eye clinic aged ≥50 were recruited for this prospective cross-sectional study. Patients completed Dry Eye Questionnaire 5, underwent tear film evaluation, and had serum androgen levels measured. The correlations between androgen levels, DES composite scores, DES symptoms, and global, lipid, and aqueous tear film parameters were evaluated. Two hundred sixty-three patients with a mean age of 69 (50-95) were examined. There was no linear association between composite DES scores (generated using latent class analysis) and androgen levels. However, eyes with high DES scores (0.95-1.0) had higher levels of sex hormone-binding globulin (P = 0.03) and lower levels of dehydroepiandrosterone sulfate (DHEAS) (P = 0.02), androstenedione (A) (P = 0.02), and androstane-3α,17β-diol glucuronide (P = 0.03) compared to eyes with intermediate (0.05-0.95) or low (0-0.05) scores. There were no strong correlations between tear film measures and androgen levels. Regarding global parameters, a weak inverse correlation was found between corneal staining and A (r = -0.17, P = 0.009). For lipid parameters, a weak correlation existed between tear breakup time (TBUT) and A (r = 0.15, P = 0.02). When considering aqueous and lipid deficiency independently, the association between TBUT and A existed only with aqueous tear deficiency (r = 0.66, P = 0.002). Regarding aqueous parameters, a weak correlation existed between Schirmer test and DHEAS (r = 0.13, P = 0.047) and A (r = 0.21, P = 0.001). There was a weak correlation between higher levels of androstenedione and healthier global, lipid, and aqueous tear film parameters. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Type I Collagen Synthesis Marker Procollagen I N-Terminal Peptide (PINP) in Prostate Cancer Patients Undergoing Intermittent Androgen Suppression

Energy Technology Data Exchange (ETDEWEB)

Hamilton, Gerhard, E-mail: gerhard.hamilton@toc.lbg.ac.at; Olszewski-Hamilton, Ulrike [Ludwig Boltzmann Cluster of Translational of Oncology, Nussdorfer Strasse 64, Vienna A-1090 (Austria); Theyer, Gerhard [Hospital Kittsee, Kittsee A-2421, Burgenland (Austria)

2011-09-15

Intermittent androgen suppression (IAS) therapy for prostate cancer patients attempts to maintain the hormone dependence of the tumor cells by cycles alternating between androgen suppression (AS) and treatment cessation till a certain prostate-specific antigen (PSA) threshold is reached. Side effects are expected to be reduced, compared to standard continuous androgen suppression (CAS) therapy. The present study examined the effect of IAS on bone metabolism by determinations of serum procollagen I N-terminal peptide (PINP), a biochemical marker of collagen synthesis. A total of 105 treatment cycles of 58 patients with prostate cancer stages ≥pT2 was studied assessing testosterone, PSA and PINP levels at monthly intervals. During phases of AS lasting for up to nine months PSA levels were reversibly reduced, indicating apoptotic regression of the prostatic tumors. Within the first cycle PINP increased at the end of the AS period and peaked in the treatment cessation phase. During the following two cycles a similar pattern was observed for PINP, except a break in collagen synthesis as indicated by low PINP levels in the first months off treatment. Therefore, measurements of the serum PINP concentration indicated increased bone matrix synthesis in response to >6 months of AS, which uninterruptedly continued into the first treatment cessation phase, with a break into each of the following two pauses. In summary, synthesis of bone matrix collagen increases while degradation decreases during off-treatment phases in patients undergoing IAS. Although a direct relationship between bone matrix turnover and risk of fractures is difficult to establish, IAS for treatment of biochemical progression of prostate tumors is expected to reduce osteoporosis in elderly men often at high risk for bone fractures representing a highly suitable patient population for this kind of therapy.

Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance.

Science.gov (United States)

Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun; Jakobsen, Marianne Antonius; Brusgaard, Klaus; Tan, Qihua; Gaster, Michael

2014-09-05

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls. Glucose transport in myotubes was comparable in patients with PCOS vs. controls and was unchanged by testosterone treatment (p=0.21 PCOS vs. controls). These results suggest that testosterone treatment of myotubes increases the aromatase and androgen receptor gene expression without affecting insulin sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

[Clinical Study of 2014 ISUP New Grade Group Classification for Prostate Cancer Patients Treated by Androgen Deprivation Therapy].

Science.gov (United States)

Uno, Masahiro; Kawase, Makoto; Kato, Daiki; Ishida, Takashi; Kato, Seiichi; Fujimoto, Yoshinori

2018-01-01

The 2014 International Society of Urological Pathology (ISUP) has proposed a new grade group (GG) classification for Gleason scores (GS). The usefulness of the new GG classification was investigated with 518 prostate cancer patients who underwent androgen deprivation therapy. According to the new GG classification, Stages B‒D and the new GG classification relapse-free rate for each stage were calculated using the Kaplan‒Meier method. The new GG classification revealed a significant difference for the relapse-free rate only between some groups. Analysis using the Cox proportional hazards model indicated that the risk of relapse was higher in GGs 4 and 5 than in GG 1. The usefulness about the relapse-free rate in androgen deprivation therapy of the 2014 ISUP new grade group classification a waits future examination.

Androgen Receptor Signaling in Bladder Cancer

OpenAIRE

Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

2017-01-01

Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in u...

Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

National Research Council Canada - National Science Library

Grigsby, James

2004-01-01

.... Our major hypothesis is the patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

National Research Council Canada - National Science Library

Grigaby, James

2003-01-01

.... Our major hypothesis is that patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

Androgen-induced cerebral venous sinus thrombosis in a young body builder: case report

Directory of Open Access Journals (Sweden)

Azimi Amir

2004-12-01

Full Text Available Abstract Background Cerebral venous sinus thrombosis is an infrequent disease with a variety of causes. Pregnancy, puerperium, contraceptive pills and intracranial infections are the most common causes. The patient may present with headache, focal neurological deficits and seizures. The clinical outcome is highly variable and treatment with heparin is advised. Case presentation The patient is a 22 year old male who presented with headache, repeated vomiting and papilledema. He was a bodybuilder doing exercise since 5 years ago, who had used nandrolone decaonoate 25 milligrams intramuscularly during the previous 5 months. Brain MRI and MRV showed superior sagital and transverse sinus thrombosis and extensive investigations did not reveal any known cause. Conclusions We suggested that androgen was the predisposing factor in our patient. Androgens may increase coagulation factors or platelet activity and cause arterial or venous thrombosis. As athletes may hide using androgens it should be considered as a predisposing factor for thrombotic events in such patients.

Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age.

Science.gov (United States)

Gleicher, Norbert; Kushnir, Vitaly A; Darmon, Sarah K; Wang, Qi; Zhang, Lin; Albertini, David F; Barad, David H

2018-03-01

A recent report described a new PCOS-like phenotype in lean older infertile women, and was characterized by high age-specific anti-Müllerian hormone (AMH) but hypo- rather than the expected hyper-androgenism. The hypo-androgenism was, furthermore, characterized of, likely, adrenal origin and autoimmune etiology. We extracted data on 708 consecutive infertility patients, and separated them into three age-strata, 42 years. In each stratum, we investigated how levels of anti-Müllerian hormone (AMH) and testosterone (T) interrelate between high-AMH (AMH ≥ 75th quantile) and normal AMH (25th-75th quantile) and low-T (total testosterone ≤19.0 ng/dL), normal-T (19.0-29.0 ng/dL) and high-T (>29.0 ng/dL). High-AMH cycles were presumed to reflect PCOS-like patients. Routine in vitro fertilization (IVF) cycle outcomes and clinical phenotypes of patients were then compared between groups with AMH and T as statistical variables. This hypo-androgenic PCOS-like phenotype already exists in age stratum androgenic PCOS phenotype that develops in comparison to controls (likely autoimmune-induced) insufficiency of the adrenal zona reticularis (low-T and low-DHEAS) and zona fasciculata (low-C), and is characterized by frequent evidence of autoimmunity. A degree of adrenal insufficiency, thus, concomitantly appears to affect adrenal androgen and, to lesser degrees, glucocorticoid production (mineralocorticoids were not investigated). Here investigated new PCOS-like phenotype demonstrates features compatible with what under Rotterdam criteria has been referred to as PCOS phenotype-D. If confirmed, the observation that the ontogeny of this phenotype already at young ages is, likely, driven by adrenal autoimmunity, supports the position of the androgen excess and PCOS society that the etiology of phenotype-D differs from that of classical hyper-androgenic PCOS of mostly ovarian etiology.

Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy

Directory of Open Access Journals (Sweden)

Lee C

2012-07-01

Full Text Available Abstract Background Prostate cancer is the most commonly diagnosed non-melanoma cancer among men. Androgen deprivation therapy (ADT has been the core therapy for men with advanced prostate cancer. It is only in recent years that clinicians began to recognize the cognitive-psychosocial side effects from ADT, which significantly compromise the quality of life of prostate cancer survivors. The objectives of the study are to determine the efficacy of a simple and accessible home-based, walking exercise program in promoting cognitive and psychosocial functions of men with prostate cancer receiving ADT. Methods A 6-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Twenty men with prostate cancer starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 6-month home-based, walking exercise program, while the Control Group will receive standard medical advice from the attending physician. The primary outcomes will be psychosocial and cognitive functions. Cognitive functions including memory, attention, working memory, and executive function will be assessed using a battery of neurocognitive tests at baseline and 6 months. Psychosocial functions including depression, anxiety and self-esteem will be assessed at baseline, 3 and 6 months using the Center for Epidemiological Studies Depression Scale, Spielberger State-Trait Anxiety Inventory, and Rosenberg Self-Esteem Scale. Discussion The significance of the cognitive-psychosocial side effects of ADT in men with prostate cancer has only been recently recognized, and the management remains unclear. This study addresses this issue by designing a simple and accessible home-based, exercise program that may potentially have significant impact on reducing the cognitive and psychosocial side effects of ADT, and ultimately

Androgen regulation of the androgen receptor coregulators

International Nuclear Information System (INIS)

Urbanucci, Alfonso; Waltering, Kati K; Suikki, Hanna E; Helenius, Merja A; Visakorpi, Tapio

2008-01-01

The critical role of the androgen receptor (AR) in the development of prostate cancer is well recognized. The transcriptional activity of AR is partly regulated by coregulatory proteins. It has been suggested that these coregulators could also be important in the progression of prostate cancer. The aim of this study was to identify coregulators whose expression is regulated by either the androgens and/or by the expression level of AR. We used empty vector and AR cDNA-transfected LNCaP cells (LNCaP-pcDNA3.1, and LNCaP-ARhi, respectively), and grew them for 4 and 24 hours in the presence of dihydrotestosterone (DHT) at various concentrations. The expression of 25 AR coregulators (SRC1, TIF2, PIAS1, PIASx, ARIP4, BRCA1, β-catenin, AIB3, AIB1, CBP, STAT1, NCoR1, AES, cyclin D1, p300, ARA24, LSD1, BAG1L, gelsolin, prohibitin, JMJD2C, JMJD1A, MAK, PAK6 and MAGE11) was then measured by using real-time quantitative RT-PCR (Q-RT-PCR). Five of the coregulators (AIB1, CBP, MAK, BRCA1 and β-catenin) showed more than 2-fold induction and 5 others (cyclin D1, gelsolin, prohibitin, JMJD1A, and JMJD2C) less than 2-fold induction. Overexpression of AR did not affect the expression of the coregulators alone. However, overexpression of AR enhanced the DHT-stimulated expression of MAK, BRCA1, AIB1 and CBP and reduced the level of expression of β-catenin, cyclinD1 and gelsolin. In conclusion, we identified 5 coactivators whose expression was induced by androgens suggesting that they could potentiate AR signaling. Overexpression of AR seems to sensitize cells for low levels of androgens

Androgen receptor status is a prognostic marker in non-basal triple negative breast cancers and determines novel therapeutic options.

Directory of Open Access Journals (Sweden)

Pierluigi Gasparini

Full Text Available Triple negative breast cancers are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapeutics. Androgen receptor has been associated with triple negative breast cancer pathogenesis, but its role in the different subtypes has not been clearly defined. We examined androgen receptor protein expression by immunohistochemical analysis in 678 breast cancers, including 396 triple negative cancers. Fifty matched lymph node metastases were also examined. Association of expression status with clinical (race, survival and pathological (basal, non-basal subtype, stage, grade features was also evaluated. In 160 triple negative breast cancers, mRNA microarray expression profiling was performed, and differences according to androgen receptor status were analyzed. In triple negative cancers the percentage of androgen receptor positive cases was lower (24.8% vs 81.6% of non-triple negative cases, especially in African American women (16.7% vs 25.5% of cancers of white women. No significant difference in androgen receptor expression was observed in primary tumors vs matched metastatic lesions. Positive androgen receptor immunoreactivity was inversely correlated with tumor grade (p<0.01 and associated with better overall patient survival (p = 0.032 in the non-basal triple negative cancer group. In the microarray study, expression of three genes (HER4, TNFSF10, CDK6 showed significant deregulation in association with androgen receptor status; eg CDK6, a novel therapeutic target in triple negative cancers, showed significantly higher expression level in androgen receptor negative cases (p<0.01. These findings confirm the prognostic impact of androgen receptor expression in non-basal triple negative breast cancers, and suggest targeting of new androgen receptor-related molecular pathways in patients with these cancers.

Stromal Androgen Receptor in Prostate Cancer Development and Progression

Science.gov (United States)

Leach, Damien A.; Buchanan, Grant

2017-01-01

Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, it has been becoming increasingly apparent that changes in AR signalling in the surrounding stroma can dramatically influence tumour cell behavior. This is reflected in the consistent finding of a strong association between stromal AR expression and patient outcomes. In this review, we explore the relationship between AR signalling in fibroblasts/myofibroblasts and prostate cancer cells in the primary site, and detail the known functions, actions, and mechanisms of fibroblast AR signaling. We conclude with an evidence-based summary of how androgen action in stroma dramatically influences disease progression. PMID:28117763

Effects of Different Exercise Modalities on Fatigue in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Year-long Randomised Controlled Trial.

Science.gov (United States)

Taaffe, Dennis R; Newton, Robert U; Spry, Nigel; Joseph, David; Chambers, Suzanne K; Gardiner, Robert A; Wall, Brad A; Cormie, Prue; Bolam, Kate A; Galvão, Daniel A

2017-08-01

Physical exercise mitigates fatigue during androgen deprivation therapy (ADT); however, the effects of different exercise prescriptions are unknown. To determine the long-term effects of different exercise modes on fatigue in prostate cancer patients undergoing ADT. Between 2009 and 2012, 163 prostate cancer patients aged 43-90 y on ADT were randomised to exercise targeting the musculoskeletal system (impact loading+resistance training; ILRT; n=58), the cardiovascular and muscular systems (aerobic+resistance training; ART; n=54), or to usual care/delayed exercise (DEL; n=51) for 12 mo across university-affiliated exercise clinics in Australia. Supervised ILRT for 12 mo, supervised ART for 6 mo followed by a 6-mo home program, and DEL received a printed booklet on exercise information for 6 mo followed by 6-mo stationary cycling exercise. Fatigue was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 36 and vitality using the Short Form-36. Analysis of variance was used to compare outcomes for groups at 6 mo and 12 mo. Fatigue was reduced (p=0.005) in ILRT at 6 mo and 12 mo (∼5 points), and in ART (p=0.005) and DEL (p=0.022) at 12 mo. Similarly, vitality increased for all groups (p≤0.001) at 12 mo (∼4 points). Those with the highest levels of fatigue and lowest vitality improved the most with exercise (p trend fatigue and enhancing vitality during ADT. Patients with the highest levels of fatigue and lowest vitality had the greatest benefits. We compared the effects of different exercise modes on fatigue in men on androgen deprivation therapy. All exercise programs reduced fatigue and enhanced vitality. We conclude that undertaking some form of exercise will help reduce fatigue, especially in those who are the most fatigued. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Prostate specific antigen (PSA) kinetic as a prognostic factor in metastatic prostate cancer receiving androgen deprivation therapy: systematic review and meta-analysis.

Science.gov (United States)

Afriansyah, Andika; Hamid, Agus Rizal Ardy Hariandy; Mochtar, Chaidir Arif; Umbas, Rainy

2018-01-01

Aim: Metastatic prostate cancer (mPCa) has a poor outcome with median survival of two to five years. The use of androgen deprivation therapy (ADT) is a gold standard in management of this stage.  Aim of this study is to analyze the prognostic value of PSA kinetics of patient treated with hormonal therapy related to survival from several published studies Method: Systematic review and meta-analysis was performed using literature searching in the electronic databases of MEDLINE, Science Direct, and Cochrane Library. Inclusion criteria were mPCa receiving ADT, a study analyzing Progression Free Survival (PFS), Overall Survival (OS), or Cancer Specific Survival (CSS) and prognostic factor of survival related to PSA kinetics (initial PSA, PSA nadir, and time to achieve nadir (TTN)). The exclusion criteria were metastatic castration resistant of prostate cancer (mCRPC) and non-metastatic disease. Generic inverse variance method was used to combine hazard ratio (HR) within the studies. Meta-analysis was performed using Review Manager 5.2 and a p-value PSA and PFS. In addition, there was no association between initial PSA and CSS/ OS. We found association of reduced PFS (HR 2.22; 95% CI 1.82 to 2.70) and OS/ CSS (HR 3.31; 95% CI 2.01-5.43) of patient with high PSA nadir. Shorter TTN was correlated with poor result of survival either PFS (HR 2.41; 95% CI 1.19 - 4.86) or CSS/ OS (HR 1.80; 95%CI  1.42 - 2.30) Conclusion: Initial PSA before starting ADT do not associated with survival in mPCa.  There is association of PSA nadir and TTN with survival.

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

Directory of Open Access Journals (Sweden)

Jennifer H. Gunter

2012-01-01

Full Text Available An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer.

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

Science.gov (United States)

Gunter, Jennifer H.; Lubik, Amy A.; McKenzie, Ian; Pollak, Michael; Nelson, Colleen C.

2012-01-01

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer. PMID:22548055

Three novel and two known androgen receptor gene mutations ...

Indian Academy of Sciences (India)

BALACHANDRAN SARANYA

with androgen insensitivity syndrome in sex-reversed XY female patients. BALACHANDRAN ..... from the subjects, their family members and controls who participated in the ..... disease, 1st edition. Springer Science + Business Media, New.

Performance comparison of two androgen receptor splice variant 7 (AR-V7) detection methods.

Science.gov (United States)

Bernemann, Christof; Steinestel, Julie; Humberg, Verena; Bögemann, Martin; Schrader, Andres Jan; Lennerz, Jochen K

2018-01-23

To compare the performance of two established androgen receptor splice variant 7 (AR-V7) mRNA detection systems, as paradoxical responses to next-generation androgen-deprivation therapy in AR-V7 mRNA-positive circulating tumour cells (CTC) of patients with castration-resistant prostate cancer (CRPC) could be related to false-positive classification using detection systems with different sensitivities. We compared the performance of two established mRNA-based AR-V7 detection technologies using either SYBR Green or TaqMan chemistries. We assessed in vitro performance using eight genitourinary cancer cell lines and serial dilutions in three AR-V7-positive prostate cancer cell lines, as well as in 32 blood samples from patients with CRPC. Both assays performed identically in the cell lines and serial dilutions showed identical diagnostic thresholds. Performance comparison in 32 clinical patient samples showed perfect concordance between the assays. In particular, both assays determined AR-V7 mRNA-positive CTCs in three patients with unexpected responses to next-generation anti-androgen therapy. Thus, technical differences between the assays can be excluded as the underlying reason for the unexpected responses to next-generation anti-androgen therapy in a subset of AR-V7 patients. Irrespective of the method used, patients with AR-V7 mRNA-positive CRPC should not be systematically precluded from an otherwise safe treatment option. © 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.

Positive HER-2 protein expression in circulating prostate cells and micro-metastasis, resistant to androgen blockage but not diethylstilbestrol

Directory of Open Access Journals (Sweden)

Nigel P Murray

2011-01-01

Full Text Available Introduction : HER-2 expression in prostate cancer is associated with a worse prognosis and is suggested to play a role in androgen resistance. We present a study of HER-2 expression in circulating tumor cells and micrometastasis in bone marrow and the effect of androgen blockage or DES in the presence of HER-2 expressing cells. Patients and Methods : A multicenter study of men with prostate cancer, treated with surgery, radiotherapy, or observation, and with or without hormone therapy. Mononuclear cells were separated from blood and bone marrow aspirate by differential centrifugation, touch preps were made from bone marrow biopsy samples. Prostate cells were detected using anti-PSA monoclonal antibody and standard immunocytochemistry. Positive samples were processed using Herceptest® to determine HER-2 expression. After 1 year, patients were re-evaluated and the findings of HER-2 expression and PSA change compared with treatment. Results : Total 199 men participated, and 97 had a second evaluation 1 year later, frequency of HER-2 expression in circulating tumor cells and micrometastasis was 18% and 21%, respectively. There was no significant difference in HER-2 expression in the pretreatment group, after radical surgery or radiotherapy or with biochemical failure. Men with androgen blockade had a significantly higher expression of HER-2 (58% (P =0.001. Of the 97 men with a second evaluation, 56 were in the observation arm, 27 androgen blockade, and 14 DES. Use of androgen blockade or DES significantly reduced serum PSA levels in comparison with observation (P =0.001. However, there was a significant increase in HER-2 expression in patients with androgen blockade (P =0.05 en comparison with observation or DES treatment. No patient with observation or DES became HER-2 positive, en comparison 4/22 patients initially HER-2 negative became HER-2 positive with androgen blockade. Conclusions : The results suggest that HER-2 positive cells are

Platelet-rich plasma in androgenic alopecia: Myth or an effective tool

Directory of Open Access Journals (Sweden)

Swapna S Khatu

2014-01-01

Full Text Available Platelet-rich plasma (PRP has become a newer method for the treatment of various types of alopecia. In this prospective study, safety, efficacy and feasibility of PRP injections in treating androgenic alopecia were assessed. Eleven patients suffering from hair loss due to androgenic alopecia and not responding to 6 months treatment with minoxidil and finasteride were included in this study. The hair pull test was performed before every treatment session. A total volume of 2-3 cc PRP was injected in the scalp by using an insulin syringe. The treatment was repeated every two weeks, for a total of four times. The outcome was assessed after 3 months by clinical examination, macroscopic photos, hair pull test and patient′s overall satisfaction. Results: A significant reduction in hair loss was observed between first and fourth injection. Hair count increased from average number of 71 hair follicular units to 93 hair follicular units. Therefore, average mean gain is 22.09 follicular units per cm 2. After the fourth session, the pull test was negative in 9 patients. Conclusion: PRP injection is a simple, cost effective and feasible treatment option for androgenic alopecia, with high overall patient satisfaction.

Evidence That Androgens Modulate Human Thymic T Cell Output

Science.gov (United States)

Olsen, Nancy J.; Kovacs, William J.

2010-01-01

Background The thymus has long been recognized as a target for the actions of androgenic hormones, but it has only been recently recognized that alterations in circulating levels of gonadal steroids might affect thymic output of T cells. We had the opportunity to examine parameters of thymic cellular output in several hypogonadal men undergoing androgen replacement therapy. Methods Circulating naive (CD4+CD45RA+) T cells were quantitated by flow cytometric analysis of peripheral blood mononuclear cells (PBMCs). Cells bearing T cell receptor excision circles (TRECs) were quantitated using real-time PCR amplification of DNA isolated from PBMCs from normal men and from hypogonadal men before and after testosterone replacement therapy. Results CD4+CD45+ (“naïve”) T cells comprised 10.5% of lymphocytes in normal males; this proportion was greatly increased in two hypogonadal men (35.5% and 44.4%). One man was studied sequentially during treatment with physiologic doses of testosterone. CD4+CD45RA+ cells fell from 37.36% to 20.05% after one month and to 12.51% after 7 months of normalized androgen levels. In two hypogonadal patients TREC levels fell by 83% and 78% after androgen replacement therapy. Conclusions Our observations indicate that the hypogonadal state is associated with increased thymic output of T cells and that this increase in recent thymic emigrants in peripheral blood is reversed by androgen replacement. PMID:21218609

Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer

International Nuclear Information System (INIS)

Lamb, David S.; Denham, James W.; Mameghan, Hedy; Joseph, David; Turner, Sandra; Matthews, John; Franklin, Ian; Atkinson, Chris; North, John; Poulsen, Michael; Kovacev, Olga; Robertson, Randall; Francis, Lynne; Christie, David; Spry, Nigel A.; Tai, K.-H.; Wynne, Chris; Duchesne, Gillian

2003-01-01

Purpose: To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer. Methods: Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals. Results: All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible. Conclusion: Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo

Cortical venous thrombosis following exogenous androgen use for bodybuilding.

Science.gov (United States)

Sveinsson, Olafur; Herrman, Lars

2013-02-05

There are only a few reports of patients developing cerebral venous sinus thrombosis (CVST) after androgen therapy. We present a young man who developed cortical venous thrombosis after using androgens to increase muscle mass. He was hospitalised for parasthesia and dyspraxia in the left hand followed by a generalised tonic-clonic seizure. At admission, he was drowsy, not fully orientated, had sensory inattention, pronation drift and a positive extensor response, all on the left side. The patient had been using anabolic steroids (dainabol 20 mg/day) for the last month for bodybuilding. CT angiography showed a right cortical venous thrombosis. Anticoagulation therapy was started with intravenous heparin for 11 days and oral anticoagulation (warfarin) thereafter. A control CT angiography 4 months later showed resolution of the thrombosis. He recovered fully.

Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

Science.gov (United States)

Coleman, Daniel J.; Van Hook, Kathryn; King, Carly J.; Schwartzman, Jacob; Lisac, Robert; Urrutia, Joshua; Sehrawat, Archana; Woodward, Josha; Wang, Nicholas J.; Gulati, Roman; Thomas, George V.; Beer, Tomasz M.; Gleave, Martin; Korkola, James E.; Gao, Lina; Heiser, Laura M.; Alumkal, Joshi J.

2016-01-01

Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. PMID:27276681

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

Directory of Open Access Journals (Sweden)

Shakespeare TP

2016-05-01

Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Rural Clinical School, Faculty of Medicine, University of New South Wales, Coffs Harbour, NSW, Australia Aim: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods: Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results: In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion: There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. Keywords: radiotherapy, IMRT, dose

Is phenytoin contraindicated in patients receiving cranial irradiation?

Energy Technology Data Exchange (ETDEWEB)

Borg, M.F. [Royal Adelaide Hospital, SA (Australia); Probert, J.C. [Auckland Hospital, Auckland (New Zealand). Dept. of Radiation Oncology; Zwi, L.J. [Auckland Univ. (New Zealand). Dept. of Medicine and Surgery

1995-02-01

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anticonvulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation. 21 refs., 2 tabs., 3 figs.

Is phenytoin contraindicated in patients receiving cranial irradiation?

International Nuclear Information System (INIS)

Borg, M.F.; Probert, J.C.; Zwi, L.J.

1995-01-01

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anticonvulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation. 21 refs., 2 tabs., 3 figs

Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes

International Nuclear Information System (INIS)

Olsen, Jan Roger; Azeem, Waqas; Hellem, Margrete Reime; Marvyin, Kristo; Hua, Yaping; Qu, Yi; Li, Lisha; Lin, Biaoyang; Ke, XI- Song; Øyan, Anne Margrete; Kalland, Karl- Henning

2016-01-01

Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable. Immortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts. A variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in

Patient satisfaction after receiving dental treatment among patients ...

African Journals Online (AJOL)

Background: Patient satisfaction is one of the indicators of the quality of care. Therefore it is one of the tools for evaluating the quality of care. Aim: To determine patient satisfaction after receiving dental treatment among patients attending public dental clinics in Dar-Es-Salaam. Material and methods: Five public dental clinics ...

Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival

Directory of Open Access Journals (Sweden)

Day Wanda V

2005-04-01

Full Text Available Abstract Background Androgens and androgen receptors (AR regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH and prostate cancer (PCa. Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA. This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells. Results The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells. Conclusion We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression.

Raised urinary glucocorticoid and adrenal androgen precursors in the urine of young hypertensive patients: possible evidence for partial glucocorticoid resistance

Science.gov (United States)

Shamim, W; Yousufuddin, M; Francis, D; Gualdiero, P; Honour, J; Anker, S; Coats, A

2001-01-01

OBJECTIVE—To evaluate urinary glucocorticoid excretion profiles in a cohort of recently diagnosed young hypertensive patients.
METHODS—After excluding patients with secondary causes, 60 individuals with premature hypertension were recruited (diagnosed by ambulatory blood pressure monitoring before the age of 36 years). In addition, 30 older hypertensive controls (age of onset > 36 years, "middle aged hypertensive controls"), and 30 normal controls (age matched to the young hypertensive group) were studied. All provided 24 hour urine collections for mass spectrometry for total cortisol metabolites and total androgen metabolites by gas chromatography.
RESULTS—Among male patients, those with premature hypertension had higher total urinary excretion of cortisol metabolites (mean (SD), 13 332 (6472) µg/day) than age matched normal controls (7270 (1788) µg/day; p = 0.00001) or middle aged hypertensive controls (8315 (3565) µg/day; p = 0.002). A similar increase was seen among the female patients, although the absolute concentrations were lower. There was no significant difference between middle aged hypertensive patients and normal controls. Urinary total androgen excretion profiles in female patients also showed an unusual increase in the premature hypertension group (2958 (1672) µg/day) compared with the other groups (middle aged hypertensive controls, 1373 (748) µg/day, p = 0.0003; normal controls, 1687 (636) µg/day, p = 0.002). In all subjects, serum sodium and creatinine concentrations were within the normal range; serum potassium concentrations were found to be low before the start of treatment.
CONCLUSIONS—Individuals presenting with premature hypertension have an abnormally high excretion of glucocorticoid metabolites in the urine. While the mechanism remains uncertain, these findings are compatible with partial resistance of the glucocorticoid receptors, with a compensatory increase in cortisol and androgen

Utilization of bone densitometry for prediction and administration of bisphosphonates to prevent osteoporosis in patients with prostate cancer without bone metastases receiving antiandrogen therapy

International Nuclear Information System (INIS)

Holt, Abby; Khan, Muhammad A; Gujja, Swetha; Govindarajan, Rangaswmy

2014-01-01

Prostate cancer subjects with prostate-specific antigen (PSA) relapse who are treated with androgen deprivation therapy (ADT) are recommended to have baseline and serial bone densitometry and receive bisphosphonates. The purpose of this community population study was to assess the utilization of bone densitometry and bisphosphonate therapy in men receiving ADT for non-metastatic prostate cancer. A cohort study of men aged 65 years or older with non-metastatic incident diagnoses of prostate cancer was obtained from the Surveillance Epidemiology End Results (SEER)-linked Medicare claims between 2004 and 2008. Claims were used to assess prescribed treatment of ADT, bone densitometry, and bisphosphonates. A total of 30,846 incident prostate cancer cases receiving ADT and aged 65 years or older had no bone metastases; 87.3% (n=26,935) on ADT did not receive either bone densitometry or bisphosphonate therapy. Three percent (n=931) of the cases on ADT received bisphosphonate therapy without ever receiving bone densitometry, 8.8% (n=2,702) of the cases on ADT received bone densitometry without receiving intravenous bisphosphonates, while nearly 1% (0.90%, n=278) of the cases on ADT received both bone densitometry and bisphosphonates. Analysis showed treatment differed by patient characteristics. Contrary to the recommendations, bone densitometry and bisphosphonate therapy are underutilized in men receiving ADT for non-metastatic prostate cancer

Three novel and two known androgen receptor gene mutations ...

Indian Academy of Sciences (India)

with androgen insensitivity syndrome in sex-reversed XY female patients. BALACHANDRAN .... Three novel AR gene mutations associated with AIS in XY sex-reversed females. Ta b le. 1 . ( contd. ) ..... disease, 1st edition. Springer Science + ...

Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.

Directory of Open Access Journals (Sweden)

Audrey Dayon

Full Text Available BACKGROUND: Sphingosine kinase-1 (SphK1 is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a

Alterations in Hydrocortisone Pharmacokinetics in a Patient With Congenital Adrenal Hyperplasia Following Bariatric Surgery

OpenAIRE

Mallappa, Ashwini; Nella, Aikaterini A.; Kumar, Parag; Brooks, Kristina M.; Perritt, Ashley F.; Ling, Alexander; Liu, Chia-Ying; Merke, Deborah P.

2017-01-01

Management of adult patients with classic congenital adrenal hyperplasia (CAH) is challenging and often complicated by obesity, metabolic syndrome, and adverse cardiovascular risk. Alterations in weight can influence cortisol kinetics. A 19-year-old woman with classic CAH and morbid obesity experienced persistent elevations of androgen levels while receiving oral glucocorticoid therapy. Control of adrenal androgens was improved with continuous subcutaneous hydrocortisone infusion therapy, but...

Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs

Science.gov (United States)

Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

2016-01-01

Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete’s urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as ‘T-equivalent’ concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact. PMID:26998755

Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs.

Science.gov (United States)

Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

2016-01-01

Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete's urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as 'T-equivalent' concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact.

Cotargeting of Androgen Synthesis and Androgen Receptor Expression as a Novel Treatment for Castration Resistant Prostate Cancer

Science.gov (United States)

2017-08-01

disease [2-4]. The major mechanism underlying the development of CRPC is the reactivation of the androgen receptor (AR), the driver of prostate cancer ...Epigenetic Activator of Androgen Receptor Expression in Castration- Resistant Prostate Cancer . Indiana Basic Urological Research (IBUR) Symposium...principal discipline(s) of the project? Androgen receptor (AR) is the driver of prostate cancer development and progression and is the validated

Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.

Science.gov (United States)

Jia, Lin; Wu, Dinglan; Wang, Yuliang; You, Wenxing; Wang, Zhu; Xiao, Lijia; Cai, Ganhui; Xu, Zhenyu; Zou, Chang; Wang, Fei; Teoh, Jeremy Yuen-Chun; Ng, Chi-Fai; Yu, Shan; Chan, Franky L

2018-03-20

The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

Comparison of the effects of 665 nm low level diode Laser Hat versus and a combination of 665 nm and 808nm low level diode Laser Scanner of hair growth in androgenic alopecia.

Science.gov (United States)

Barikbin, Behrooz; Khodamrdi, Zeinab; Kholoosi, Leila; Akhgri, Mohammad Reza; Haj Abbasi, Majid; Hajabbasi, Mojgan; Razzaghi, Zahra; Akbarpour, Samaneh

2017-05-17

This study aimed to evaluate the effectiveness of a combined set of low level diode laser scanner (665 nm and 808nm) on hair growth, and assessment of safety and effectiveness of a new laser scanner on hair growth treatment procedure in androgenic alopecia. 90 patients (18 to 70 years) with androgenic alopecia were randomized into three groups. The first group (n=30) received 655 nm red light using laser hat, the second group (n=30) received 655 nm red laser plus 808 nm infrared laser using a laser scanner of hair growth device (with the patent number: 77733) and the third group (n=30) received no laser as the control group. Patients in laser scanner group had better results and showed a higher increase in terminal hair density compared with laser hat group (mean of 9.61 versus 9.16 per cm 2 ). We found significant decrease in terminal hair density from baseline in control group (mean -1.8 per cm 2 , plaser scanner of the hair growth group compared with laser hat and the control group. The study showed that treatment with new laser devise had a promising result without any observable adverse effects.

Androgen circle of polycystic ovary syndrome.

Science.gov (United States)

Homburg, Roy

2009-07-01

Although the aetiology of polycystic ovary syndrome (PCOS) is still not known and the search for causative genes is proving elusive, it is generally agreed that hyperandrogenism is at the heart of the syndrome. Here, it is proposed that excess androgens are the root cause of PCOS starting from their influence on the female fetus in programming gene expression, producing the characteristic signs and symptoms which are then exacerbated by a propagation of excess ovarian androgen production from multiple small follicles, anovulation and insulin resistance in the reproductive life-span, thus setting up a vicious perpetual circle of androgen excess. This opinion paper, rather than being a full-scale review, is intentionally biased in support of this hypothesis that androgen excess is the 'root of all evil' in PCOS; in the hope that its acceptance could lead to more direct treatment of the syndrome in all its facets rather than the symptomatic treatment of side effects of androgen excess that we are addressing today.

A national multicenter phase 2 study of prostate-specific antigen (PSA) pox virus vaccine with sequential androgen ablation therapy in patients with PSA progression: ECOG 9802.

Science.gov (United States)

DiPaola, Robert S; Chen, Yu-Hui; Bubley, Glenn J; Stein, Mark N; Hahn, Noah M; Carducci, Michael A; Lattime, Edmund C; Gulley, James L; Arlen, Philip M; Butterfield, Lisa H; Wilding, George

2015-09-01

E9802 was a phase 2 multi-institution study conducted to evaluate the safety and effectiveness of vaccinia and fowlpox prostate-specific antigen (PSA) vaccine (step 1) followed by combination with androgen ablation therapy (step 2) in patients with PSA progression without visible metastasis. To test the hypothesis that vaccine therapy in this early disease setting will be safe and have a biochemical effect that would support future studies of immunotherapy in patients with minimal disease burden. Patients who had PSA progression following local therapy were treated with PROSTVAC-V (vaccinia)/TRICOM on cycle 1 followed by PROSTVAC-F (fowlpox)/TRICOM for subsequent cycles in combination with granulocyte-macrophage colony-stimulating factor (step 1). Androgen ablation was added on progression (step 2). Step 1 primary end points included progression at 6 mo and characterization of change in PSA velocity pretreatment to post-treatment. Step 2 end points included PSA response with combined vaccine and androgen ablation. In step 1, 25 of 40 eligible patients (63%) were progression free at 6 mo after registration (90% confidence interval [CI], 48-75). The median pretreatment PSA velocity was 0.13 log(PSA)/mo, in contrast to median postregistration velocity of 0.09 log(PSA)/mo (p=0.02), which is an increase in median PSA doubling time from 5.3 mo to 7.7 mo. No grade ≥4 treatment-related toxicity was observed. In the 27 patients eligible and treated for step 2, 20 patients achieved a complete response (CR) at 7 mo (CR rate: 74%; 90% CI, 57-87). Although supportive of larger studies in the cooperative group setting, this study is limited by the small number of patients and the absence of a control group as in a phase 3 study. A viral PSA vaccine can be administered safely in the multi-institutional cooperative group setting to patients with minimal disease volume alone and combined with androgen ablation, supporting the feasibility of future phase 3 studies in this

A unique mosaic Turner syndrome patient with androgen receptor gene derived marker chromosome.

Science.gov (United States)

Kalkan, Rasime; Özdağ, Nermin; Bundak, Rüveyde; Çirakoğlu, Ayşe; Serakinci, Nedime

2016-01-01

Patients with Turner syndrome are generally characterized by having short stature with no secondary sexual characteristics. Some abnormalities, such as webbed neck, renal malformations (>50%) and cardiac defects (10%) are less common. The intelligence of these patients is considered normal. Non-mosaic monosomy X is observed in approximately 45% of postnatal patients with Turner syndrome and the rest of the patients have structural abnormalities or mosaicism involving 46,X,i(Xq), 45,X/46,XX, 45,X and other variants. The phenotype of 45,X/46,X,+mar individuals varies by the genetic continent and degree of the mosaicism. The gene content of the marker chromosome is the most important when correlating the phenotype with the genotype. Here we present an 11-year-old female who was referred for evaluation of her short stature and learning disabilities. Conventional cytogenetic investigation showed a mosaic 45,X/46,X,+mar karyotype. Fluorescence in situ hybridization showed that the marker chromosome originated from the X chromosome within the androgen receptor (AR) and X-inactive specific transcript (XIST) genes. Therefore, it is possible that aberrant activation of the marker chromosome, compromising the AR and XIST genes, may modify the Turner syndrome phenotype.

Cognitive Impairment in Men with Prostate Cancer Treated with Androgen Deprivation Therapy: A Systematic Review and Meta-Analysis.

Science.gov (United States)

Sun, Maxine; Cole, Alexander P; Hanna, Nawar; Mucci, Lorelei A; Berry, Donna L; Basaria, Shehzad; Ahern, David K; Kibel, Adam S; Choueiri, Toni K; Trinh, Quoc-Dien

2018-06-01

Use of androgen deprivation therapy may increase the risk of cognitive impairment in men with prostate cancer. We performed a systematic review of the risk of overall cognitive impairment as an outcome in men receiving androgen deprivation therapy for prostate cancer. Studies were identified through PubMed®, MEDLINE®, PsycINFO®, Cochrane Library and Web of Knowledge/Science™. Articles were included if they 1) were published in English, 2) had subjects treated for prostate cancer with androgen deprivation therapy, 3) incorporated longitudinal comparisons and 4) used control groups. In addition, prospective studies were required to assess an established cognitive related end point using International Cognition and Cancer Task Force criteria defining impaired cognitive performance as scoring 1.5 or more standard deviations below published norms on 2 or more tests, or scoring 2.0 or more standard deviations below published norms on at least 1 test. The effect of androgen deprivation therapy on cognitive impairment was pooled using a random effects model. Of 221 abstracts 26 were selected for full text review, and 2 prospective and 4 retrospective studies were analyzed. Androgen deprivation therapy was not associated with overall cognitive impairment when the prospective cohort studies were pooled (OR 1.57, 95% CI 0.50 to 4.92, p = 0.44) with significant heterogeneity between estimates (I 2 = 83%). In retrospective data the relative risk of any cognitive impairment, including senile dementia and Alzheimer disease, was increased in men receiving androgen deprivation therapy, although the difference was not statistically significant (HR 1.28, 95% CI 0.93 to 1.76, p = 0.13) with moderate heterogeneity between estimates (I 2 = 67%). Analyses between overall cognitive impairment and use of androgen deprivation therapy defined according to International Cognition and Cancer Task Force criteria in a pooled analysis were inconclusive. In retrospective cohort studies the

Androgen-deprivation therapy does not impact cause-specific or overall survival after permanent prostate brachytherapy

International Nuclear Information System (INIS)

Merrick, Gregory S.; Butler, Wayne M.; Wallner, Kent E.; Galbreath, Robert W.; Allen, Zachariah A. M.S.; Adamovich, Edward

2006-01-01

Purpose: To determine if androgen-deprivation therapy (ADT) has an impact on cause-specific, biochemical progression-free, or overall survival after prostate brachytherapy. Methods and Materials: From April 1995 through June 2002, 938 consecutive patients underwent brachytherapy for clinical Stage T1b to T3a (2002 AJCC) prostate cancer. All patients underwent brachytherapy more than 3 years before analysis. A total of 382 patients (40.7%) received ADT with a duration of 6 months or less in 277 and more than 6 months in 105. The median follow-up was 5.4 years. Multiple clinical, treatment, and dosimetric parameters were evaluated as predictors of cause-specific, biochemical progression-free, and overall survival. Results: The 10-year cause-specific, biochemical progression-free, and overall survival rates for the entire cohort were 96.4%, 95.9%, and 78.1%, respectively. Except for biochemical progression-free survival in high-risk patients, ADT did not statistically impact any of the three survival categories. A Cox linear-regression analysis demonstrated that Gleason score was the best predictor of cause-specific survival, whereas percent-positive biopsies, prostate volume, and risk group predicted for biochemical progression-free survival. Patient age and tobacco use were the strongest predictors of overall survival. One hundred two patients have died, with 80 of the deaths a result of cardiovascular disease (54) and second malignancies (26). To date, only 12 patients have died of metastatic prostate cancer. Conclusions: After brachytherapy, androgen-deprivation therapy did not have an impact on cause-specific or overall survival for any risk group; however, ADT had a beneficial effect on biochemical progression-free survival in high-risk patients. Cardiovascular disease and second malignancies far outweighed prostate cancer as competing causes of death

A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice.

Science.gov (United States)

Chisamore, Michael J; Gentile, Michael A; Dillon, Gregory Michael; Baran, Matthew; Gambone, Carlo; Riley, Sean; Schmidt, Azriel; Flores, Osvaldo; Wilkinson, Hilary; Alves, Stephen E

2016-10-01

which may provide potent anti-androgenic activity at the prostate yet protective activity on skeletal muscle and behavior in patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features.

Science.gov (United States)

Daan, N M P; Jaspers, L; Koster, M P H; Broekmans, F J M; de Rijke, Y B; Franco, O H; Laven, J S E; Kavousi, M; Fauser, B C J M

2015-10-01

regarding the role of androgens in the development of CVD and potential modulatory effects of BMI is required. N.M.P.D. is supported by the Dutch Heart Foundation (grant number 2013T083). L.J. and O.H.F. work in ErasmusAGE, a center for aging research across the life course, funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA. M.K. is supported by the AXA Research Fund. Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, Merck Sharpe & Dome, Organon, Schering Plough and Serono. In the last 5 years, B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Actavis, COGI, Euroscreen, Ferring, Finox, Genovum, Gedeon-Richter, Merck-Serono, OvaScience, Pantharei Bioscience, PregLem, Roche, Uteron and Watson laboratories. With regard to potential conflicts of interest, there is nothing further to disclose. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

Directory of Open Access Journals (Sweden)

Rosenberg JE

2012-01-01

Full Text Available Yasser Rehman1, Jonathan E Rosenberg21Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA, USA; 2Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC, which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17. This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.Keywords: CRPC, abiraterone, CYP17, inhibitors, androgens, castration resistant prostate cancer

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

Science.gov (United States)

2017-10-01

response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and...hormones that play a critical role in stimulating prostate cancer growth. Androgens activate a protein called the androgen receptor (AR), which...treat patients with prostate cancer, over time the tumors become resistant to the drugs, leaving few treatment options. The goal of this proposal is to

Testosterone regulates keratin 33B expression in rat penis growth through androgen receptor signaling

OpenAIRE

Yan-Min Ma; Kai-Jie Wu; Qiang Dang; Qi Shi; Yang Gao; Peng Guo; Shan Xu; Xin-Yang Wang; Da-Lin He; Yong-Guang Gong

2014-01-01

Androgen therapy is the mainstay of treatment for the hypogonadotropic hypogonadal micropenis because it obviously enhances penis growth in prepubescent microphallic patients. However, the molecular mechanisms of androgen treatment leading to penis growth are still largely unknown. To clarify this well-known phenomenon, we successfully generated a castrated male Sprague Dawley rat model at puberty followed by testosterone administration. Interestingly, compared with the control group, testost...

Differential effects of androgens on coronary blood flow regulation and arteriolar diameter in intact and castrated swine

Directory of Open Access Journals (Sweden)

O’Connor Erin K

2012-05-01

Full Text Available Abstract Background Low endogenous testosterone levels have been shown to be a risk factor for the development of cardiovascular disease and cardiovascular benefits associated with testosterone replacement therapy are being advocated; however, the effects of endogenous testosterone levels on acute coronary vasomotor responses to androgen administration are not clear. The objective of this study was to compare the effects of acute androgen administration on in vivo coronary conductance and in vitro coronary microvascular diameter in intact and castrated male swine. Methods Pigs received intracoronary infusions of physiologic levels (1–100 nM of testosterone, the metabolite 5α-dihydrotestosterone, and the epimer epitestosterone while left anterior descending coronary blood flow and mean arterial pressure were continuously monitored. Following sacrifice, coronary arterioles were isolated, cannulated, and exposed to physiologic concentrations (1–100 nM of testosterone, 5α-dihydrotestosterone, and epitestosterone. To evaluate effects of the androgen receptor on acute androgen dilation responses, real-time PCR and immunohistochemistry for androgen receptor were performed on conduit and resistance coronary vessels. Results In vivo, testosterone and 5α-dihydrotestosterone produced greater increases in coronary conductance in the intact compared to the castrated males. In vitro, percent maximal dilation of microvessels was similar between intact and castrated males for testosterone and 5α-dihydrotestosterone. In both studies epitestosterone produced significant increases in conductance and microvessel diameter from baseline in the intact males. Androgen receptor mRNA expression and immunohistochemical staining were similar in intact and castrated males. Conclusions Acute coronary vascular responses to exogenous androgen administration are increased by endogenous testosterone, an effect unrelated to changes in androgen receptor expression.

Cardiovascular Adaptations to Recreational Football Training in Men with Type 2 Diabetes, Untrained Elderly Men and in Men with Prostate Cancer Receiving Androgen Deprivation Therapy

DEFF Research Database (Denmark)

Schmidt, Jakob Friis

Numerous people in the general population are not suffuciently physically active and the use of new exercise training modalities which could promote physically active lifestyles are important. The present PhD thesis includes studies , which investigated the effect of recreational football training...... in middle-aged men with type 2 diabetes, 65-75-year-old untrained men, men with prostate cancer receiving androgen deprivation therapy and the effect of life-long participation in football training in veteran football players. The primary purpose was to evaluate the structure and function of the heart...... by ultrasound (echocardiography) and in three studies football training was shown to have marked positive effects on the heart function. In addition cardiorespiratory fitness, blood pressure, resting heart rate and peripheral microvascular function was evaluated and in men with type 2 diabetes, elderly...

Kennedy's disease and partial androgen insensitivity syndrome. Report of 4 cases and literature review.

Science.gov (United States)

Valera Yepes, Rocío; Virgili Casas, Maria; Povedano Panades, Monica; Guerrero Gual, Mireia; Villabona Artero, Carles

2015-05-01

Kennedy's disease, also known as bulbospinal muscular atrophy, is a rare, X-linked recessive neurodegenerative disorder affecting adult males. It is caused by expansion of an unstable cytosine-adenine-guanine tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12, and is characterized by spinal motor neuron progressive degeneration. Endocrinologically, these patients often have the features of hypogonadism associated to the androgen insensitivity syndrome, particularly its partial forms. We report 4 cases with the typical neurological presentation, consisting of slowly progressing generalized muscle weakness with atrophy and bulbar muscle involvement; these patients also had several endocrine manifestations; the most common non-neurological manifestation was gynecomastia. In all cases reported, molecular analysis showed an abnormal cytosine-adenine-guanine triplet repeat expansion in the androgen receptor gene. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Minimal percentage of dose received by 90% of the urethra (%UD90) is the most significant predictor of PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer.

Science.gov (United States)

Tanaka, Nobumichi; Asakawa, Isao; Fujimoto, Kiyohide; Anai, Satoshi; Hirayama, Akihide; Hasegawa, Masatoshi; Konishi, Noboru; Hirao, Yoshihiko

2012-09-14

To clarify the significant clinicopathological and postdosimetric parameters to predict PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer. We studied 200 consecutive patients who received LDR-brachytherapy between July 2004 and November 2008. Of them, 137 patients did not receive neoadjuvant or adjuvant androgen deprivation therapy. One hundred and forty-two patients were treated with LDR-brachytherapy alone, and 58 were treated with LDR-brachytherapy in combination with external beam radiation therapy. The cut-off value of PSA bounce was 0.1 ng/mL. The incidence, time, height, and duration of PSA bounce were investigated. Clinicopathological and postdosimetric parameters were evaluated to elucidate independent factors to predict PSA bounce in hormone-naïve patients who underwent LDR-brachytherapy alone. Fifty patients (25%) showed PSA bounce and 10 patients (5%) showed PSA failure. The median time, height, and duration of PSA bounce were 17 months, 0.29 ng/mL, and 7.0 months, respectively. In 103 hormone-naïve patients treated with LDR-brachytherapy alone, and univariate Cox proportional regression hazard model indicated that age and minimal percentage of the dose received by 30% and 90% of the urethra were independent predictors of PSA bounce. With a multivariate Cox proportional regression hazard model, minimal percentage of the dose received by 90% of the urethra was the most significant parameter of PSA bounce. Minimal percentage of the dose received by 90% of the urethra was the most significant predictor of PSA bounce in hormone-naïve patients treated with LDR-brachytherapy alone.

Nutritional survey of neoplasm patients receiving radiotherapy

International Nuclear Information System (INIS)

Li Xinli; Zhu Shengtao

2001-01-01

Objective: In order to know the nutriture of neoplasm patients receiving radiotherapy and give nutritional guidance properly, the authors make the following survey. Methods: A dietary survey of twenty-four-hour retrospective method was used; The patients' activity was recorded and their twenty-four hours caloric consumption was calculated. Results: Of all the patients, the intake of protein is more than recommended, percentage of calorific proportion is about 15%-19% of gross caloric. A larger portion of patients' caloric intake, especially female patients, is lower than caloric consumption. Among all the patients, the intake of vegetables is not enough; The consumption of milk and milky products is lower; it is common and serious that neoplasm patients receiving radiotherapy have vitamine and mineral's scarcity. Conclusions: Nutriture of neoplasm patients is not optimistic, it is imperative to improve their nutriture

Use of body and beard donor hair in surgical treatment of androgenic alopecia

Directory of Open Access Journals (Sweden)

Arvind Poswal

2013-01-01

Full Text Available Objectives: Follicular unit transplant is a widely used surgical treatment for androgenic alopecia. However, for patients with extensive hair loss (Norwood 5 and above, scalp donor hair are not sufficient to cover all areas of baldness. This study aims to assess suitability of beard and body donor hair when transplanted to the scalp. Materials and Methods: In 35 male patients having varying degrees of androgenic alopecia, body and beard donor hair were extracted by follicular unit extraction method (under local anesthesia. They were transplanted in different locations of the scalp. Follow-up was carried out at various intervals (6 months to 2 years. The hairs were observed for colour, curl and calibre. Results: In all the patients, there was no change in the colour, curl or calibre of the transplanted body/beard hair. They maintained the same characteristics as in their original location. Conclusion: Body and beard hair can be used as additional donor resource for treating androgenic alopecia. These hairs, however, do not change their colour, curl, and shaft diameter (calibre. Thus, proper planning is a must when using the different types of donor hair for transplanting.

Genetics Home Reference: androgen insensitivity syndrome

Science.gov (United States)

... Androgen insensitivity syndrome is a condition that affects sexual development before birth and during puberty. People with this ... characteristics or signs of both male and female sexual development. Complete androgen insensitivity syndrome occurs when the body ...

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

Directory of Open Access Journals (Sweden)

Shakespeare TP

2016-03-01

Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Faculty of Medicine, Rural Clinical School, The University of New South Wales, Coffs Harbour, New South Wales, Australia Background: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings: In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion: There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. Keywords: radiotherapy, IMRT, dose, dose escalation, dose de-escalation, androgen deprivation therapy

Hypochlorite Oxidation of Select Androgenic Steroids

Science.gov (United States)

Steroid hormones are vital for regulation of various biological functions including sexual development. Elevated concentrations of natural and synthetic androgenic steroids have been shown to adversely affect normal development in indigenous aqueous species. Androgens and their s...

Adrenal androgen secretion and dopaminergic activity in anorexia nervosa.

Science.gov (United States)

Devesa, J; Pérez-Fernández, R; Bokser, L; Gaudiero, G J; Lima, L; Casanueva, F F

1988-01-01

The aim of the present study was to investigate if the postulated deficient adrenal androgen secretion in Anorexia Nervosa (AN), could be associated with a status of sustained dopaminergic hyperactivity. The adrenal responses to ACTH and PRL response to dopaminergic receptor blockade were studied in seven patients with Anorexia Nervosa and seven regularly menstruating women. AN patients showed lower baseline DHEA-sulphate (DHEA-S), androstenedione (Adione) and prolactin (PRL) levels than controls. The response to ACTH revealed evidences of significantly decreased 17-20 desmolase activity in AN, with apparent predominance of glucocorticoid over androgenic pathways relative to controls. Because dopaminergic receptor blockade with Domperidone (DOM) showed intense dopaminergic hyperactivity in AN, we postulate that the adrenal regression seen in the disease is the consequence of a reduced zona reticularis as a consequence of the lack of trophic support by PRL and/or intermediate lobe proopiomelanocortin (IL-POMC). This is consistent with our previous results in pre-adrenarchal dogs and rabbits.

Hypersensitivity reactions in patients receiving hemodialysis.

Science.gov (United States)

Butani, Lavjay; Calogiuri, Gianfranco

2017-06-01

To describe hypersensitivity reactions in patients receiving maintenance hemodialysis. PubMed search of articles published during the past 30 years with an emphasis on publications in the past decade. Case reports and review articles describing hypersensitivity reactions in the context of hemodialysis. Pharmacologic agents are the most common identifiable cause of hypersensitivity reactions in patients receiving hemodialysis. These include iron, erythropoietin, and heparin, which can cause anaphylactic or pseudoallergic reactions, and topical antibiotics and anesthetics, which lead to delayed-type hypersensitivity reactions. Many hypersensitivity reactions are triggered by complement activation and increased bradykinin resulting from contact system activation, especially in the context of angiotensin-converting enzyme inhibitor use. Several alternative pharmacologic preparations and dialyzer membranes are available, such that once an etiology for the reaction is established, recurrences can be prevented without affecting the quality of care provided to patients. Although hypersensitivity reactions are uncommon in patients receiving hemodialysis, they can be life-threatening. Moreover, considering the large prevalence of the end-stage renal disease population, the implications of such reactions are enormous. Most reactions are pseudoallergic and not mediated by immunoglobulin E. The multiplicity of potential exposures and the complexity of the environment to which patients on dialysis are exposed make it challenging to identify the precise cause of these reactions. Great diligence is needed to investigate hypersensitivity reactions to avoid recurrence in this high-risk population. Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Significance of pretreatment cardiovascular morbidity as a risk factor during treatment with parenteral oestrogen or combined androgen deprivation of 915 patients with metastasized prostate cancer

DEFF Research Database (Denmark)

Johansson, Robert; Damber, Jan Erik; Hagerman, Inger

2011-01-01

This study aimed to evaluate prognostic risk factors for cardiovascular events during treatment of metastatic prostate cancer patients with high-dose parenteral polyoestradiol phosphate (PEP, Estradurin®) or combined androgen deprivation (CAD) with special emphasis on pretreatment cardiovascular...

Modulation of Androgen Receptor Transcriptional Activity

NARCIS (Netherlands)

H.Y. Wong (Hao Yun)

2009-01-01

textabstractAndrogens, testosterone (T) and 5a-dihydrotestosterone (DHT), are important for male and female physiology, in particular for male sexual differentiation, development of secondary male characteristics and spermatogenesis. These hormones exert their actions by binding to the androgen

Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

Energy Technology Data Exchange (ETDEWEB)

Kaini, Ramesh R. [Department of Biochemistry and Molecular Biology and UNM Cancer and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM (United States); Hu, Chien-An A., E-mail: AHu@salud.unm.edu [Department of Biochemistry and Molecular Biology and UNM Cancer and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM (United States)

2012-08-24

Highlights: Black-Right-Pointing-Pointer Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. Black-Right-Pointing-Pointer Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. Black-Right-Pointing-Pointer Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. Black-Right-Pointing-Pointer Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

International Nuclear Information System (INIS)

Kaini, Ramesh R.; Hu, Chien-An A.

2012-01-01

Highlights: ► Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. ► Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. ► Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. ► Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

Causes, Patterns, and Severity of Androgen Excess in 1205 Consecutively Recruited Women.

Science.gov (United States)

Elhassan, Yasir S; Idkowiak, Jan; Smith, Karen; Asia, Miriam; Gleeson, Helena; Webster, Rachel; Arlt, Wiebke; O'Reilly, Michael W

2018-03-01

Androgen excess in women is predominantly due to underlying polycystic ovary syndrome (PCOS). However, there is a lack of clarity regarding patterns and severity of androgen excess that should be considered predictive of non-PCOS pathology. We examined the diagnostic utility of simultaneous measurement of serum dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), and testosterone (T) to delineate biochemical signatures and cutoffs predictive of non-PCOS disorders in women with androgen excess. Retrospective review of all women undergoing serum androgen measurement at a large tertiary referral center between 2012 and 2016. Serum A4 and T were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased serum androgen underwent phenotyping by clinical notes review. In 1205 women, DHEAS, A4, and T were measured simultaneously. PCOS was the most common diagnosis in premenopausal (89%) and postmenopausal women (29%). A4 was increased in all adrenocortical carcinoma (ACC) cases (n = 15) and T in all ovarian hyperthecosis (OHT) cases (n = 7); all but one case of congenital adrenal hyperplasia (CAH; n = 18) were identified by increased levels of A4 and/or T. In premenopausal women, CAH was a prevalent cause of severe A4 (59%) and T (43%) excess; severe DHEAS excess was predominantly due to PCOS (80%). In postmenopausal women, all cases of severe DHEAS and A4 excess were caused by ACC and severe T excess equally by ACC and OHT. Pattern and severity of androgen excess are important predictors of non-PCOS pathology and may be used to guide further investigations as appropriate.

Progression of puberty after initiation of androgen therapy in patients with idiopathic hypogonadotropic hypogonadism

Directory of Open Access Journals (Sweden)

Bindu Kulshreshtha

2013-01-01

Full Text Available Background: Onset of puberty in boys usually occurs by 14 years of age. Some boys may exhibit delayed sexual maturation till about 17-18 years of age. However, pubertal onset beyond 18 years of age is exceedingly rare. Materials and Methods: Patients diagnosed as idiopathic hypogonadotropic hypogonadism (IHH who had onset of puberty (increase in testicular volume >10 ml while on androgen therapy were studied. These patients were evaluated prospectively. Results: There were nine subjects that were included in the study. The pre-therapy testicular volumes ranged from 3 to 6 ml. Luteinizing hormone (LH levels increased from 1.2 ± 0.96 to 2.8 ± 1.0 IU/L, follicular stimulating hormone (FSH levels increased from 1.5 ± 0.79 to 3.5 ± 1.9 IU/L, and testosterone increased from 0.36 ± 0.16 to 3.4 ± 2.1 ng/ml. Three out of nine patients had testosterone levels below 3 ng/ml. Conclusion: Our present study indicates that pubertal development can occur in patients presenting with hypogonadotropic hypogonadism after 18 years of age. However, acquired pubertal status may be subnormal

Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells

Science.gov (United States)

Schatten, H.; Ripple, M.; Balczon, R.; Weindruch, R.; Chakrabarti, A.; Taylor, M.; Hueser, C. N.

2000-01-01

We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. Copyright 2000 Wiley-Liss, Inc.

A PRACTICAL APPROACH TO THE DETECTION OF ANDROGEN RECEPTOR GENE-MUTATIONS AND PEDIGREE ANALYSIS IN FAMILIES WITH X-LINKED ANDROGEN INSENSITIVITY

NARCIS (Netherlands)

RISSTALPERS, C; HOOGENBOEZEM, T; SLEDDENS, HFBM; VERLEUNMOOIJMAN, MCT; DEGENHART, HJ; DROP, SLS; HALLEY, DJJ; Oosterwijk, Jan; HODGINS, MB; TRAPMAN, J; BRINKMANN, AO

Androgen insensitivity syndrome (AIS) is an X-linked disorder in which defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. This survey reports the analysis of 11 AIS subjects. The androgen receptor gene of

A practical approach to the detection of androgen receptor gene mutations and pedigree analysis in families with x-linked androgen insensitivity

NARCIS (Netherlands)

Ris-Stalpers, C.; Hoogenboezem, T.; Sleddens, H. F.; Verleun-Mooijman, M. C.; Degenhart, H. J.; Drop, S. L.; Halley, D. J.; Oosterwijk, J. C.; Hodgins, M. B.; Trapman, J.

1994-01-01

Androgen insensitivity syndrome (AIS) is an X-linked disorder in which defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. This survey reports the analysis of 11 AIS subjects. The androgen receptor gene of

Androgens as double-edged swords: Induction and suppression of follicular development.

Science.gov (United States)

Pan, Jie-Xue; Zhang, Jun-Yu; Ke, Zhang-Hong; Wang, Fang-Fang; Barry, John A; Hardiman, Paul J; Qu, Fan

2015-01-01

Androgens, which are mediated via the androgen receptor (AR), play important roles in normal follicular development and female fertility. However, just like a double-edged sword, besides the positive effects of androgen on follicular development, abnormal androgen levels, especially as in hyperandrogenism, seriously suppress normal follicular development. A crucial balance exists between the importance of androgens in follicular development and their negative effects when in excess. As the first meiotic division and epigenetic reprogramming are two critical events in oogenesis, abnormal androgen levels or deficiency in androgen/AR signaling in the ovary may affect these vital events. Oocytes have a tendency to develop genomic instability, thus resulting in an increasing incidence of unpredictable adult diseases. Although many studies have explored the effects of androgens and AR on follicular development, the conclusions are controversial and there has been no thorough review of this topic. This review focuses on the roles of androgens in the physiological process of follicular development, summarizes new insights into the roles of androgens in the arrested development of follicles, and discusses the potential risk of adult diseases originating from abnormal follicular androgen levels or androgen receptor signals, which may determine areas for future studies.

Androgens regulate gene expression in avian skeletal muscles.

Directory of Open Access Journals (Sweden)

Matthew J Fuxjager

Full Text Available Circulating androgens in adult reproductively active male vertebrates influence a diversity of organ systems and thus are considered costly. Recently, we obtained evidence that androgen receptors (AR are expressed in several skeletal muscles of three passeriform birds, the golden-collared manakin (Manacus vitellinus, zebra finch (Taenopygia guttata, and ochre-bellied flycatcher (Mionectes oleagieus. Because skeletal muscles that control wing movement make up the bulk of a bird's body mass, evidence for widespread effects of androgen action on these muscles would greatly expand the functional impact of androgens beyond their well-characterized effects on relatively discrete targets throughout the avian body. To investigate this issue, we use quantitative PCR (qPCR to determine if androgens alter gene mRNA expression patterns in wing musculature of wild golden-collared manakins and captive zebra finches. In manakins, the androgen testosterone (T up-regulated expression of parvalbumin (PV and insulin-like growth factor I (IGF-I, two genes whose products enhance cellular Ca(2+ cycling and hypertrophy of skeletal muscle fibers. In T-treated zebra finches, the anti-androgen flutamide blunted PV and IGF-I expression. These results suggest that certain transcriptional effects of androgen action via AR are conserved in passerine skeletal muscle tissue. When we examined wing muscles of manakins, zebra finches and ochre-bellied flycatchers, we found that expression of PV and IGF-I varied across species and in a manner consistent with a function for AR-dependent gene regulation. Together, these findings imply that androgens have the potential to act on avian muscle in a way that may enhance the physicality required for successful reproduction.

Football training improves lean body mass in men with prostate cancer undergoing androgen deprivation therapy

DEFF Research Database (Denmark)

Uth, J; Hornstrup, Therese; Schmidt, Jakob Friis

2014-01-01

Androgen deprivation therapy (ADT) remains a cornerstone in the management of patients with prostate cancer (PCa) despite adverse effects on body composition and functional parameters. We compared the effects of football training with standard care in PCa patients managed with ADT (> 6 months......). Fifty-seven men aged 67 (range: 43-74) were randomly assigned to a football group (FG, n = 29) or a usual care control group (CON, n = 28). The primary outcome was change in lean body mass (LBM) assessed by dual-energy X-ray absorptiometry scanning. Secondary outcomes included changes in knee.......7%; 95%CI 1.3-0.0; P = 0.06), but these changes were not significantly different from CON. In conclusion, football training over 12 weeks improved LBM and muscle strength compared with usual care in men with prostate cancer receiving ADT....

Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

Science.gov (United States)

Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

2012-01-01

The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

Immunoexpression of androgen receptors and aromatase in testes of patient with Klinefelter's syndrome.

Directory of Open Access Journals (Sweden)

Stanisław Fracki

2005-02-01

Full Text Available Klinefelter's syndrome (47, XXY is the most common chromosome aneuploidy in men and is usually characterized by underdeveloped testes and sterility. The aim of the present study was to detect cellular distribution of androgen receptors (AR and aromatase in testes of patient with KS. The tissue sections were processed for morphological and immunohistochemical staining. Additionally, levels of FSH, LH, PRL, estradiol, and testosterone were measured in the plasma. Morphological analysis revealed a complete absence of spermatogenesis. No germ cells were present in seminiferous tubules. In some tubules, nests of apparently degenerating Sertoli cells were found. In the interstitium, Leydig cell hyperplasia was observed. Using immunohistochemistry, nuclear AR staining was detected in Sertoli cells and peritubular cells, whereas in Leydig cells the staining was exclusively cytoplasmic. The immunostaining of aromatase was detected in the cytoplasm of Sertoli cells and Leydig cells. Increased levels of gonadotropins and decreased level of testosterone concomitantly with the cytoplasmic localization of AR in Leydig cells might contribute to the impaired testicular function in patient with KS.

Network analysis of an in vitro model of androgen-resistance in prostate cancer

International Nuclear Information System (INIS)

Detchokul, Sujitra; Elangovan, Aparna; Crampin, Edmund J.; Davis, Melissa J.; Frauman, Albert G.

2015-01-01

The development of androgen resistance is a major limitation to androgen deprivation treatment in prostate cancer. We have developed an in vitro model of androgen-resistance to characterise molecular changes occurring as androgen resistance evolves over time. Our aim is to understand biological network profiles of transcriptomic changes occurring during the transition to androgen-resistance and to validate these changes between our in vitro model and clinical datasets (paired samples before and after androgen-deprivation therapy of patients with advanced prostate cancer). We established an androgen-independent subline from LNCaP cells by prolonged exposure to androgen-deprivation. We examined phenotypic profiles and performed RNA-sequencing. The reads generated were compared to human clinical samples and were analysed using differential expression, pathway analysis and protein-protein interaction networks. After 24 weeks of androgen-deprivation, LNCaP cells had increased proliferative and invasive behaviour compared to parental LNCaP, and its growth was no longer responsive to androgen. We identified key genes and pathways that overlap between our cell line and clinical RNA sequencing datasets and analysed the overlapping protein-protein interaction network that shared the same pattern of behaviour in both datasets. Mechanisms bypassing androgen receptor signalling pathways are significantly enriched. Several steroid hormone receptors are differentially expressed in both datasets. In particular, the progesterone receptor is significantly differentially expressed and is part of the interaction network disrupted in both datasets. Other signalling pathways commonly altered in prostate cancer, MAPK and PI3K-Akt pathways, are significantly enriched in both datasets. The overlap between the human and cell-line differential expression profiles and protein networks was statistically significant showing that the cell-line model reproduces molecular patterns observed in

Complete Androgen Insensitivity Syndrome in Three Sisters

Directory of Open Access Journals (Sweden)

Levent Verim

2014-01-01

Full Text Available Disorders of sexual development (DSD are congenital anomalies due to atypical development of chromosomes, gonads and anatomy. Complete androgen insensitivity syndrome (CAIS, also known as testicular feminization (TF is a rare DSD disease. The majority of CAIS patients apply to hospital with the complaint of primary amenorrhea or infertility. Given that CAIS patients are all phenotypically female while having 46, XY karyotypes, CAIS diagnosis should be disclosed in an age-appropriate manner preferably by a mental health professional. Cases are reported here for three 46XY siblings consistent with CAIS.

Molecular mechanisms of androgen receptor functions

NARCIS (Netherlands)

K. Steketee (Karine)

2007-01-01

textabstractThe androgens testosterone (T) and dihydrotestosterone (DHT) are steroid hormones, which are necessary for development and maintenance of the functions of the male sex organs, including the prostate. Androgens also play an important role in benign abnormalities of the prostate and in the

Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

International Nuclear Information System (INIS)

Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A.; Pinilla, Mabel G.; Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C.; McNerney, Eileen M.; Onate, Sergio A.

2015-01-01

Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

Energy Technology Data Exchange (ETDEWEB)

Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Pinilla, Mabel G. [Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C. [Department of Physiopathology, School of Biological Sciences, University of Concepcion, Concepcion (Chile); McNerney, Eileen M. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Onate, Sergio A., E-mail: sergio.onate@udec.cl [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Department of Urology, State University of New York at Buffalo, NY (United States)

2015-11-27

Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

Compounds from Cynomorium songaricum with Estrogenic and Androgenic Activities Suppress the Oestrogen/Androgen-Induced BPH Process.

Science.gov (United States)

Wang, Xueni; Tao, Rui; Yang, Jing; Miao, Lin; Wang, Yu; Munyangaju, Jose Edouard; Wichai, Nuttapong; Wang, Hong; Zhu, Yan; Liu, Erwei; Chang, Yanxu; Gao, Xiumei

2017-01-01

To investigate the phytoestrogenic and phytoandrogenic activities of compounds isolated from CS and uncover the role of CS in prevention of oestrogen/androgen-induced BPH. Cells were treated with CS compounds, and immunofluorescence assay was performed to detect the nuclear translocation of ER α or AR in MCF-7 or LNCaP cells; luciferase reporter assay was performed to detect ERs or AR transcriptional activity in HeLa or AD293 cells; MTT assay was performed to detect the cell proliferation of MCF-7 or LNCaP cells. Oestrogen/androgen-induced BPH model was established in rat and the anti-BPH, anti-estrogenic, and anti-androgenic activities of CS in vivo were further investigated. The nuclear translocation of ER α was stimulated by nine CS compounds, three of which also stimulated AR translocation. The transcriptional activities of ER α and ER β were induced by five compounds, within which only ECG induced AR transcriptional activity as well. Besides, ECG stimulated the proliferation of both MCF-7 cells and LNCaP cells. CS extract suppressed oestrogen/androgen-induced BPH progress in vivo by downregulation of E2 and T level in serum and alteration of the expressions of ER α , ER β , and AR in the prostate. Our data demonstrates that compounds from CS exhibit phytoestrogenic and phytoandrogenic activities, which may contribute to inhibiting the oestrogen/androgen-induced BPH development.

Androgen regulated genes in human prostate xenografts in mice: relation to BPH and prostate cancer.

Directory of Open Access Journals (Sweden)

Harold D Love

2009-12-01

Full Text Available Benign prostatic hyperplasia (BPH and prostate carcinoma (CaP are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1 highly expressed in prostate, 2 had significant expression changes in response to androgens, and, 3 encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues.

Expression of androgen-binding protein (ABP) in human cardiac myocytes.

Science.gov (United States)

Schock, H W; Herbert, Z; Sigusch, H; Figulla, H R; Jirikowski, G F; Lotze, U

2006-04-01

Cardiomyocytes are known to be androgen targets. Changing systemic steroid levels are thought to be linked to various cardiac ailments, including dilated cardiomyopathy (DCM). The mode of action of gonadal steroid hormones on the human heart is unknown to date. In the present study, we used high-resolution immunocytochemistry on semithin sections (1 microm thick), IN SITU hybridization, and mass spectrometry to investigate the expression of androgen-binding protein (ABP) in human myocardial biopsies taken from male patients with DCM. We observed distinct cytoplasmic ABP immunoreactivity in a fraction of the myocytes. IN SITU hybridization with synthetic oligonucleotide probes revealed specific hybridization signals in these cells. A portion of the ABP-positive cells contained immunostaining for androgen receptor. With SELDI TOF mass spectrometry of affinity purified tissue extracts of human myocardium, we confirmed the presence of a 50 kDa protein similar to ABP. Our observations provide evidence of an intrinsic expression of ABP in human heart. ABP may be secreted from myocytes in a paracrine manner perhaps to influence the bioavailabity of gonadal steroids in myocardium.

Effects of orlistat on serum androgen levels among iranian obese women with polycystic ovarian syndrome.

Science.gov (United States)

Salehpour, Saghar; Hosseini, Sedighe; Nazari, Leila; Saharkhiz, Nasrin; Zademodarres, Shahrzad

2018-05-14

Polycystic ovary syndrome is one of the most common endocrinopathies in young women, and it affects 6% to 8% of women in reproductive age. Hyperandrogenism is the hallmark of polycystic ovary syndrome. The aim of the present study was to evaluate the effects of orlistat on weight loss and serum androgen levels among Iranian women with polycystic ovary syndrome. The present study was carried out in the clinic of Infertility and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Thirty-two patients with polycystic ovary syndrome were randomly enrolled. We measured serum androgens (Testosterone, 17α-hydroxyprogesterone, dehydroepiandrosterone and sex hormone-binding globulin) before and after 12 weeks of treatment with orlistat. We used the Rotterdam Criteria for all patients and transvaginal sonography was performed. The mean age of patients was 27.75±6.22 and the mean body mass index was 32.69±0.94 kg/m2. Comparing with baseline, treatment with orlistat resulted in a significant reduction in weight, BMI, and waist circumference (p=0.001). We also found a remarkable reduction in total testosterone levels (p>0.001). Treatment improved the sex hormone-binding globulin plasma levels, but the improvement was not statistically significant. There was no reduction in other androgen levels. This study showed a significant reduction of weight and total testosterone level - the most important androgen in polycystic ovary syndrome - after 12 weeks of treatment with orlistat. Therefore, it seems that a short course of orlistat can be useful in the management of patients with polycystic ovary syndrome.

Enhanced Androgen Signaling With Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture

National Research Council Canada - National Science Library

Wiren, Kristine M; Jepsen, Karl

2006-01-01

.... We genetically engineered transgenic mice in which androgen receptor (AR) overexpression is skeletally targeted in two separate models to better understand the role of androgen signaling directly in bone...

Illicit use of androgens and other hormones: recent advances.

Science.gov (United States)

Kanayama, Gen; Pope, Harrison G

2012-06-01

To summarize recent advances in studies of illicit use of androgens and other hormones. Androgens and other appearance-enhancing and performance-enhancing substances are widely abused worldwide. Three notable clusters of findings have emerged in this field in recent years. First, studies almost unanimously find that androgen users engage in polypharmacy, often ingesting other hormones (e.g., human growth hormone, thyroid hormones, and insulin), ergo/thermogenic drugs (e.g., caffeine, ephedrine, and clenbuterol), and classical drugs of abuse (e.g., cannabis, opiates, and cocaine). Second, reports of long-term psychiatric and medical adverse effects of androgens continue to accumulate. In cardiovascular research particularly, controlled studies have begun to supersede anecdotal evidence, strengthening the case that androgens (possibly acting synergistically with other abused drugs) may cause significant morbidity and even mortality. Third, it is increasingly recognized that androgen use may lead to a dependence syndrome with both psychological and physiological origins. Androgen dependence likely affects some millions of individuals worldwide, and arguably represents the least studied major class of illicit drug dependence. Given mounting evidence of the adverse effects of androgens and associated polypharmacy, this topic will likely represent an expanding area of research and an issue of growing public health concern.

Complete androgen insensitivity syndrome with paratesticular leiomyoma: A case report

Energy Technology Data Exchange (ETDEWEB)

Lee, Ji Hoon; Oh, Hyung Woo; Lee, Mi Ja; Lim, Dong Hoon [Chosun University College of Medicine, Gwangju (Korea, Republic of)

2017-03-15

Complete androgen insensitivity syndrome (AIS) is a rare, X-linked recessive disorder. Patients with AIS may develop primary amenorrhea due to androgen receptor resistance, resulting in a normal female phenotype and male (XY) karyotype. We report a case of a 30-year-old woman who was diagnosed with complete AIS. Ultrasonography and magnetic resonance imaging revealed bilateral inguinal cryptorchidism and no ovaries and uterus. After gonadectomy, the inguinal mass was confirmed as testicular atrophy with hamartomatous proliferation of Leydig cells and paratesticular leiomyoma. Although these tumors have been reported in association with AIS, this is the first case of paratesticular leiomyoma with hamartomatous proliferation of Leydig cells in atrophic testes being reported in Korea.

Complete androgen insensitivity syndrome with paratesticular leiomyoma: A case report

International Nuclear Information System (INIS)

Lee, Ji Hoon; Oh, Hyung Woo; Lee, Mi Ja; Lim, Dong Hoon

2017-01-01

Complete androgen insensitivity syndrome (AIS) is a rare, X-linked recessive disorder. Patients with AIS may develop primary amenorrhea due to androgen receptor resistance, resulting in a normal female phenotype and male (XY) karyotype. We report a case of a 30-year-old woman who was diagnosed with complete AIS. Ultrasonography and magnetic resonance imaging revealed bilateral inguinal cryptorchidism and no ovaries and uterus. After gonadectomy, the inguinal mass was confirmed as testicular atrophy with hamartomatous proliferation of Leydig cells and paratesticular leiomyoma. Although these tumors have been reported in association with AIS, this is the first case of paratesticular leiomyoma with hamartomatous proliferation of Leydig cells in atrophic testes being reported in Korea

[Efficacy and safety of hormonal therapy with androgens (androgel) in men with erectile dysfunction, partial androgen deficiency of aging male and cardiovascular diseases].

Science.gov (United States)

Kalinchenko, S Iu; Vorslov, L O; Aglamazian, N L; Morgunov, L Iu

2007-01-01

Partial androgen deficiency of aging male (PADAM) manifests with sexual dysfunction and is associated with many diseases, primarily, cardiovascular. After the age of 30-40 a testosterone level falls 1-2% a year. The number of men with testosterone deficiency grows from 8% in 40-60-year-olds to 85% at the age over 80 years. Low testosterone correlates with such risk factors of cardiovascular diseases as dyslipidemia, atherosclerosis, low fibrinolysis, insulin resistance and abdominal obesity. Correction of androgenic deficiency can be conducted with the drug androgel which represents a new system of transdermal testosterone delivery. In contrast to vasoactive drugs, androgel affects pathogenetic mechanisms of erectile dysfunction and thus attenuates factors of cardiovascular risk. Androgel is used externally and is more effective than intramuscular and oral analogues. Also, the drug improves lipid spectrum. By activating lipolysis, testosterone reduces the amount of visceral fat thus lowering insulin resistance. A vasodilating effect of androgel positively influences cardiovascular system and penile vessels. The drug acts fast, is effective and safe. Therefore, it can be recommended for correction of erectile dysfunction in patients with old age androgen deficiency and concurrent cardiovascular diseases.

National survey addressing the information needs of primary care physicians: Side effect management of patients on androgen deprivation therapy.

Science.gov (United States)

Soeyonggo, Tony; Locke, Jennifer; Giudice, Maria Elizabeth Del; Alibhai, Shabbir; Fleshner, Neil Eric; Warde, Padraig

2014-03-01

Androgen deprivation therapy (ADT) is a common treatment for prostate cancer with numerous side effects. We assess primary care physicians' (PCPs) knowledge of ADT side effects and their interest in increasing their knowledge in this area. A list of active Canadian PCPs was obtained using the Canadian Medical Directory. A cross-sectional survey was distributed to 600 randomly selected physicians. We collected PCPs' demographic information, experience with ADT management, knowledge regarding ADT side effects and desired sources for obtaining knowledge on ADT management. In total, we received 103 completed questionnaires. Of these, 89% of PCPs had patients on ADT. One-third of respondents prescribed ADT and over half of them administered ADT annually. Thirty-eight percent felt their knowledge of ADT side effects was inadequate and 50% felt uncomfortable counselling patients on ADT. Many PCPs were less familiar with the incidence of functional side effects of ADT (i.e., hot flashes, fatigue and erectile dysfunction) compared to life-threatening side effects (i.e., cardiovascular events, metabolic syndrome, fractures). In terms of increasing their knowledge of ADT side effects, 82% of PCPs would use educational resources if they were available (52% and 32% preferred continued medical education [CME] events and educational pamphlets, respectively). PCPs play an important role in managing ADT side effects. There is poor awareness of the prevalence of ADT side effects, and many are uncomfortable in managing these side effects. These areas may be addressed through CME programs and educational pamphlets.

Growth of a progesterone receptor-positive meningioma in a female patient with congenital adrenal hyperplasia.

Science.gov (United States)

O'Shea, T; Crowley, R K; Farrell, M; MacNally, S; Govender, P; Feeney, J; Gibney, J; Sherlock, M

2016-01-01

Meningioma growth has been previously described in patients receiving oestrogen/progestogen therapy. We describe the clinical, radiological, biochemical and pathologic findings in a 45-year-old woman with congenital adrenal hyperplasia secondary to a defect in the 21-hydroxylase enzyme who had chronic poor adherence to glucocorticoid therapy with consequent virilisation. The patient presented with a frontal headache and marked right-sided proptosis. Laboratory findings demonstrated androgen excess with a testosterone of 18.1 nmol/L (0-1.5 nmol) and 17-Hydroxyprogesterone >180 nmol/L (transsexual patients undergoing therapy with high-dose oestrogen and progestogens. Progesterone receptor positivity has been described previously in meningiomas. 17-Hydroxyprogesterone is elevated in CAH and has affinity and biological activity at the progesterone receptor. Therefore, we hypothesise that patients who have long-standing increased adrenal androgen precursor concentrations may be at risk of meningioma growth. Patients with long-standing CAH (particularly if not optimally controlled) may present with other complications, which may be related to long-standing elevated androgen or decreased glucocorticoid levels.Chronic poor control of CAH is associated with adrenal myelolipoma and adrenal rest tissue tumours.Meningiomas are sensitive to endocrine stimuli including progesterone, oestrogen and androgens as they express the relevant receptors.

Enhanced mucosal reactions in AIDS patients receiving oropharyngeal irradiation

Energy Technology Data Exchange (ETDEWEB)

Watkins, E.B.; Findlay, P.; Gelmann, E.; Lane, H.C.; Zabell, A.

1987-09-01

The oropharynx and hypopharynx are common sites of involvement in AIDS patients with mucocutaneous Kaposi's sarcoma. The radiotherapist is often asked to intervene with these patients due to problems with pain, difficulty in swallowing, or impending airway obstruction. We have noted an unexpected decrease in normal tissue tolerance of the oropharyngeal mucosa to irradiation in AIDS patients treated in our department. Data on 12 patients with AIDS and Kaposi's sarcoma receiving oropharyngeal irradiation are presented here. Doses ranged from 1000 cGy to 1800 cGy delivered in 150-300 cGy fractions. Seven of eight patients receiving doses of 1200 cGy or more developed some degree of mucositis, four of these developed mucositis severe enough to require termination of treatment. All patients in this study received some form of systemic therapy during the course of their disease, but no influence on mucosal response to irradiation was noted. Four patients received total body skin electron treatments, but no effect on degree of mucositis was seen. Presence or absence of oral candidiasis was not an obvious factor in the radiation response of the oral mucosa in these patients. T4 counts were done on 9 of the 12 patients. Although the timing of the T4 counts was quite variable, no correlation with immune status and degree of mucositis was found. The degree of mucositis seen in these patients occurred at doses much lower than expected based on normal tissue tolerances seen in other patient populations receiving head and neck irradiations. We believe that the ability of the oral mucosa to repair radiation damage is somehow altered in patients with AIDS.

Enhanced mucosal reactions in AIDS patients receiving oropharyngeal irradiation

International Nuclear Information System (INIS)

Watkins, E.B.; Findlay, P.; Gelmann, E.; Lane, H.C.; Zabell, A.

1987-01-01

The oropharynx and hypopharynx are common sites of involvement in AIDS patients with mucocutaneous Kaposi's sarcoma. The radiotherapist is often asked to intervene with these patients due to problems with pain, difficulty in swallowing, or impending airway obstruction. We have noted an unexpected decrease in normal tissue tolerance of the oropharyngeal mucosa to irradiation in AIDS patients treated in our department. Data on 12 patients with AIDS and Kaposi's sarcoma receiving oropharyngeal irradiation are presented here. Doses ranged from 1000 cGy to 1800 cGy delivered in 150-300 cGy fractions. Seven of eight patients receiving doses of 1200 cGy or more developed some degree of mucositis, four of these developed mucositis severe enough to require termination of treatment. All patients in this study received some form of systemic therapy during the course of their disease, but no influence on mucosal response to irradiation was noted. Four patients received total body skin electron treatments, but no effect on degree of mucositis was seen. Presence or absence of oral candidiasis was not an obvious factor in the radiation response of the oral mucosa in these patients. T4 counts were done on 9 of the 12 patients. Although the timing of the T4 counts was quite variable, no correlation with immune status and degree of mucositis was found. The degree of mucositis seen in these patients occurred at doses much lower than expected based on normal tissue tolerances seen in other patient populations receiving head and neck irradiations. We believe that the ability of the oral mucosa to repair radiation damage is somehow altered in patients with AIDS

Androgen receptor-related diseases: what do we know?

Science.gov (United States)

Shukla, G C; Plaga, A R; Shankar, E; Gupta, S

2016-05-01

The androgen receptor (AR) and the androgen-AR signaling pathway play a significant role in male sexual differentiation and the development and function of male reproductive and non-reproductive organs. Because of AR's widely varied and important roles, its abnormalities have been identified in various diseases such as androgen insensitivity syndrome, spinal bulbar muscular atrophy, benign prostatic hyperplasia, and prostate cancer. This review provides an overview of the function of androgens and androgen-AR mediated diseases. In addition, the diseases delineated above are discussed with respect to their association with mutations and other post-transcriptional modifications in the AR. Finally, we present an introduction to the potential therapeutic application of most recent pharmaceuticals including miRNAs in prostate cancer that specifically target the transactivation function of the AR at post-transcriptional stages. © 2016 American Society of Andrology and European Academy of Andrology.

Pharmacodynamics of selective androgen receptor modulators.

Science.gov (United States)

Yin, Donghua; Gao, Wenqing; Kearbey, Jeffrey D; Xu, Huiping; Chung, Kiwon; He, Yali; Marhefka, Craig A; Veverka, Karen A; Miller, Duane D; Dalton, James T

2003-03-01

The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.

Transcript Levels of Androgen Receptor Variant 7 and Ubiquitin-Conjugating Enzyme 2C in Hormone Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer.

Science.gov (United States)

Lee, Chan Ho; Ku, Ja Yoon; Ha, Jung Min; Bae, Sun Sik; Lee, Jeong Zoo; Kim, Choung-Soo; Ha, Hong Koo

2017-01-01

This study is designed to identify the androgen receptor variant 7 (AR-V7) status, clinical significance of AR-V7 in hormone sensitive prostate cancer (HSPC). Then, we evaluated AR-V7 and changes of its target gene, ubiquitin-conjugating enzyme E2C (UBE2C) which is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin-conjugating enzyme, in castration-resistant prostate cancer (CRPC) in serial tumor biopsies from patients receiving androgen deprivation therapy. We used RT-PCR and Q-PCR assay to evaluate AR-V7, androgen receptor full length (AR-FL), and UBE2C in tumor biopsies from patients with HSPC and CRPC. We examined associations between mRNA expression of AR-V7 and clinicopathologic factors. Furthermore, to identify other potential genes involved in the development of CRPC, RNA sequencing was conducted, using paired prostate cancer (PCa) tissues obtained immediately prior to treatment and at the time of therapeutic resistance. A total of 13 HSPC patients and three CRPC patients were enrolled. Neither a high Gleason score (score of 8 and 9) nor a high risk of PCa (a high risk of locally advanced PCa according to NCCN guidelines) was correlated with mRNA expression of AR-V7 in HSPC (P = 0.153 and P = 0.215). The mRNA expression of AR-FL, but not AR-V7, was significantly associated with the mRNA expression of UBE2C level in HSPC (P = 0.007). However, increased expression of AR-V7, not AR-FL, paralleled increased expression of UBE2C in the CRPC specimens (P = 0.03). AR-V7 expression status before ADT was likely related to shorter CRPC development in patients treating ADT. The result of the RNA-sequencing analysis using serial samples from the same patient before and after castration demonstrated an increased level of the PI3K regulatory subunit 1 (P = 0.018). Our study revealed the role of UBE2C as a marker of the androgen signaling pathway in PCa. Differential gene expression analysis using serial samples from the same patient

Discovery and therapeutic promise of selective androgen receptor modulators.

Science.gov (United States)

Chen, Jiyun; Kim, Juhyun; Dalton, James T

2005-06-01

Androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis. The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic properties. The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies with advantages including oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and the lack of steroid-related side effects.

Challenges in clinical and laboratory diagnosis of androgen insensitivity syndrome: a case report

Directory of Open Access Journals (Sweden)

Silva Daniela M

2011-09-01

Full Text Available Abstract Introduction Androgen is a generic term usually applied to describe a group of sex steroid hormones. Androgens are responsible for male sex differentiation during embryogenesis at the sixth or seventh week of gestation, triggering the development of the testes and penis in male fetuses, and are directed by the testicular determining factor: the gene SRY (sex determining region on Y chromosome located on the short arm of chromosome Y. The differentiation of male external genitalia (penis, scrotum and penile urethra occurs between the 9th and 13th weeks of pregnancy and requires adequate concentration of testosterone and the conversion of this to another more potent androgen, dihydrotestosterone, through the action of 5α-reductase in target tissues. Case presentation This report describes the case of a teenage girl presenting with a male karyotype, and aims to determine the extension of the mutation that affected the AR gene. A Caucasian girl aged 15 was referred to our laboratory for genetic testing due to primary amenorrhea. Physical examination, karyotype testing and molecular analysis of the androgen receptor were critical in making the correct diagnosis of complete androgen insensitivity syndrome. Conclusions Sex determination and differentiation depend on a cascade of events that begins with the establishment of chromosomal sex at fertilization and ends with sexual maturation at puberty, subsequently leading to fertility. Mutations affecting the AR gene may cause either complete or partial androgen insensitivity syndrome. The case reported here is consistent with complete androgen insensitivity syndrome, misdiagnosed at birth, and consequently our patient was raised both socially and educationally as a female. It is critical that health care providers understand the importance of properly diagnosing a newborn manifesting ambiguous genitalia. Furthermore, a child with a pseudohermaphrodite phenotype should always undergo adequate

Prospective study of exercise intervention in prostate cancer patients on androgen deprivation therapy

International Nuclear Information System (INIS)

Beydoun, Nadine; Bucci, Joseph A.; Chin, Yaw S.; Spry, Nigel; Newton, Robert; Galvão, Daniel A.

2014-01-01

Androgen deprivation therapy (ADT) is an important component of modern prostate cancer treatment. Survival benefits from neo-adjuvant and adjuvant hormones may take years to manifest, and balancing this with potential morbidity of therapy can be challenging. This study aimed to assess whether education and short-term combined aerobic and resistance exercises could help to ameliorate the adverse side effects of ADT. Eight hundred fifty-nine patients with relapsed or metastatic prostate cancer on leuprorelin acetate were allocated to three interventional streams based on patient preference and medical fitness: supervised group (Face-to-Face) exercise sessions, home-based (At Home) exercise or a support programme for those incapable of exercising (Support). Patients enrolled onto Face to Face underwent measurement of body composition and cardiorespiratory fitness variables at baseline and programme completion. Patients in the exercise streams were surveyed to determine the programme's impact on physical fitness and well-being. Statistically significant improvements (p<0.001) were seen in all measured cardiorespiratory fitness and strength variables. Programme attrition rates were low (75/859; 8.7%), the primary reason for withdrawal being discontinuation of hormones (70%). Programme satisfaction was high, with 98% of surveyed patients reporting a positive impact on fitness and 97% planning to continue exercising after programme completion. At 6 months, improved physical and emotional well-being was reported by 93 and 79% of patients, respectively. A short-term structured exercise intervention results in high compliance and significant improvements in muscle strength and cardiorespiratory fitness in prostate cancer patients on ADT.

A spilt head study of efficacy of placebo versus platelet-rich plasma injections in the treatment of androgenic alopecia

Directory of Open Access Journals (Sweden)

Dilip Kachhawa

2017-01-01

Full Text Available Background: Platelet-rich plasma (PRP is an autologous concentration of human platelets contained in a small volume of plasma with haemostatic and tissue repairing effects. Being enriched by various growth factors, PRP has become the focus of attention in numerous fields of medicine. Androgenic alopecia (AGA is a common chronic hair loss disorder, characterised by progressive hair loss. Despite the therapeutic options available, there is low patient compliance and satisfaction rate. The topical and often systemic adverse effects of therapy has lead to the search of new treatment options for AGA. Recently, PRP has received growing attention as a potential therapeutic tool for hair loss. Aim: To compare the efficacy of placebo versus PRP injections in the treatment of male AGA. Patients and Methods: Fifty male patients with AGA (Grade III to VI were enrolled in the study. PRP was prepared using the double-spin method and injected in the androgen-related areas of scalp on the left side. Normal saline was injected on the right side in a similar fashion. Treatment sessions were performed with an interval of 21 days, and six sittings were completed for every patient. Results: Hair loss reduced with evidence of new hair growth. Digital image analysis showed an overall improvement in hair density and quality as lanugo-like hair became thicker, normal hair. An improvement in hair density, quality and thickness on trichoscopy was noted. Conclusion: Our data suggest that PRP injections have therapeutic effect on male pattern hair loss with no major side effects and high patient satisfaction overall.

Possibilities оf use of testosterone undecanoate in treatment in stroke male patients with type 2 diabetes mellitus

Directory of Open Access Journals (Sweden)

L. Yu. Morgunov

2014-11-01

Full Text Available We have studied 154 men with the first hemispheric ischemic stroke. Clinical and laboratory studies have revealed the androgen deficiency in 66.3 %, with its frequency higher in patients with diabetes mellitus type 2 (50 % and 26.3 %, respectively. Forty-two men with diabetes mellitus type 2 and acquired androgenic deficit received replacing treatment with testosterone undecanoate. After 2 years from the beginning of treatment, there were the decrease in clinical severity of androgenic deficit, the increase of total and free testosterone levels, and muscle power in the main group compared to the controls. Body mass index, glycated hemoglobin, cholesterol, triglycerides, low density lipoproteins have decreased as well. Secondary stroke has developed in 3 (7.1 % patients of the main group and in 5 (16.6 % controls. The treatment with androgens has a positive effect on risk factors of secondary ischemic stroke. It is an effective method for improvement of social adaptation of men survived after the stroke..

Anabolic-androgenic steroids for alcoholic liver disease

DEFF Research Database (Denmark)

Rambaldi, Andrea; Iaquinto, Gaetano; Gluud, Christian

2002-01-01

The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease.......The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease....

Impact of Androgen Deprivation Therapy on Self-Reported Cognitive Function in Men with Prostate Cancer.

Science.gov (United States)

Marzouk, Shireen; Naglie, Gary; Tomlinson, George; Duff Canning, Sarah; Breunis, Henriette; Timilshina, Narhari; Alibhai, Shabbir M H

2018-03-01

Although androgen deprivation therapy is widely used to treat prostate cancer, its effects on cognitive function are unclear. To our knowledge no prior report has examined the impact of androgen deprivation therapy on self-reported cognitive function. Three groups of men 50 years old or older who were matched on age and education were enrolled in the study, including 81 with prostate cancer starting on continuous androgen deprivation therapy, 84 controls with prostate cancer not receiving androgen deprivation therapy and 85 healthy controls. Two scales from the FACT-Cog (Functional Assessment of Cancer Therapy-Cognitive subscale) version 3 were used to assess self-reported cognitive function. Changes in cognitive scores with time were analyzed by 2 approaches, including 1) multivariable regression and 2) calculation of the proportion of subjects per group with a decrease of 1 SD or more. Multivariable regression was applied to assess predictors of a decline in self-reported cognitive function. We also examined relationships between the FACT-Cog and a neuropsychological battery of 15 tests. Mean participant age was 69 years (range 50 to 87). The mean educational level was 15 years (range 8 to 24). FACT-Cog scores were similar at baseline across the cohorts. Neither analytical approach revealed that androgen deprivation therapy was associated with changes in self-reported cognitive function on either FACT-Cog scale. Mood and fatigue correlated with changes in self-reported cognitive function. The relationship between self-reported and objective cognitive measures was weak (maximum Spearman correlation coefficient 0.14) and only 2 of 30 correlations were statistically significant. A total of 12 months of androgen deprivation therapy were not associated with self-reported cognitive function changes in older men with nonmetastatic prostate cancer. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights

Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy.

Science.gov (United States)

Hvid, Thine; Winding, Kamilla; Rinnov, Anders; Dejgaard, Thomas; Thomsen, Carsten; Iversen, Peter; Brasso, Klaus; Mikines, Kari J; van Hall, Gerrit; Lindegaard, Birgitte; Solomon, Thomas P J; Pedersen, Bente K

2013-10-01

Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (PBody weight (Pbody fat mass (FM) (Pbody mass (P=0.99) was unchanged. Additionally, reductions were observed in abdominal (Pcancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men.

ING3 promotes prostate cancer growth by activating the androgen receptor.

Science.gov (United States)

Nabbi, Arash; McClurg, Urszula L; Thalappilly, Subhash; Almami, Amal; Mobahat, Mahsa; Bismar, Tarek A; Binda, Olivier; Riabowol, Karl T

2017-05-16

The androgen receptor (AR) is a major driver of prostate cancer, and increased AR levels and co-activators of the receptor promote the development of prostate cancer. INhibitor of Growth (ING) proteins target lysine acetyltransferase or lysine deacetylase complexes to the histone H3K4Me3 mark of active transcription, to affect chromatin structure and gene expression. ING3 is a stoichiometric member of the TIP60 lysine acetyltransferase complex implicated in prostate cancer development. Biopsies of 265 patients with prostate cancer were stained for ING3, pan-cytokeratin, and DNA. LNCaP and C4-2 androgen-responsive cells were used for in vitro assays including immunoprecipitation, western blotting, Luciferase reporter assay and quantitative polymerase chain reaction. Cell viability and migration assays were performed in prostate cancer cell lines using scrambled siRNA or siRNA targeting ING3. We find that ING3 levels and AR activity positively correlate in prostate cancer. ING3 potentiates androgen effects, increasing expression of androgen-regulated genes and androgen response element-driven reporters to promote growth and anchorage-independent growth. Conversely, ING3 knockdown inhibits prostate cancer cell growth and invasion. ING3 activates the AR by serving as a scaffold to increase interaction between TIP60 and the AR in the cytoplasm, enhancing receptor acetylation and translocation to the nucleus. Activation is independent of ING3's ability to target the TIP60 complex to H3K4Me3, identifying a previously unknown chromatin-independent cytoplasmic activity for ING3. In agreement with in vitro observations, analysis of The Cancer Genome Atlas (TCGA) data (n = 498) and a prostate cancer tissue microarray (n = 256) show that ING3 levels are higher in aggressive prostate cancers, with high levels of ING3 predicting shorter patient survival in a low AR subgroup. Including ING3 levels with currently used indicators such as the Gleason score provides more

Testosterone regulates keratin 33B expression in rat penis growth through androgen receptor signaling.

Science.gov (United States)

Ma, Yan-Min; Wu, Kai-Jie; Dang, Qiang; Shi, Qi; Gao, Yang; Guo, Peng; Xu, Shan; Wang, Xin-Yang; He, Da-Lin; Gong, Yong-Guang

2014-01-01

Androgen therapy is the mainstay of treatment for the hypogonadotropic hypogonadal micropenis because it obviously enhances penis growth in prepubescent microphallic patients. However, the molecular mechanisms of androgen treatment leading to penis growth are still largely unknown. To clarify this well-known phenomenon, we successfully generated a castrated male Sprague Dawley rat model at puberty followed by testosterone administration. Interestingly, compared with the control group, testosterone treatment stimulated a dose-dependent increase of penis weight, length, and width in castrated rats accompanied with a dramatic recovery of the pathological changes of the penis. Mechanistically, testosterone administration substantially increased the expression of androgen receptor (AR) protein. Increased AR protein in the penis could subsequently initiate transcription of its target genes, including keratin 33B (Krt33b). Importantly, we demonstrated that KRT33B is generally expressed in the rat penis and that most KRT33B expression is cytoplasmic. Furthermore, AR could directly modulate its expression by binding to a putative androgen response element sequence of the Krt33b promoter. Overall, this study reveals a novel mechanism facilitating penis growth after testosterone treatment in precastrated prepubescent animals, in which androgen enhances the expression of AR protein as well as its target genes, such as Krt33b.

Testosterone regulates keratin 33B expression in rat penis growth through androgen receptor signaling

Directory of Open Access Journals (Sweden)

Yan-Min Ma

2014-12-01

Full Text Available Androgen therapy is the mainstay of treatment for the hypogonadotropic hypogonadal micropenis because it obviously enhances penis growth in prepubescent microphallic patients. However, the molecular mechanisms of androgen treatment leading to penis growth are still largely unknown. To clarify this well-known phenomenon, we successfully generated a castrated male Sprague Dawley rat model at puberty followed by testosterone administration. Interestingly, compared with the control group, testosterone treatment stimulated a dose-dependent increase of penis weight, length, and width in castrated rats accompanied with a dramatic recovery of the pathological changes of the penis. Mechanistically, testosterone administration substantially increased the expression of androgen receptor (AR protein. Increased AR protein in the penis could subsequently initiate transcription of its target genes, including keratin 33B (Krt33b. Importantly, we demonstrated that KRT33B is generally expressed in the rat penis and that most KRT33B expression is cytoplasmic. Furthermore, AR could directly modulate its expression by binding to a putative androgen response element sequence of the Krt33b promoter. Overall, this study reveals a novel mechanism facilitating penis growth after testosterone treatment in precastrated prepubescent animals, in which androgen enhances the expression of AR protein as well as its target genes, such as Krt33b.

Effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with idiopathic hypogonadotropic hypogonadism.

Science.gov (United States)

Doğan, Berçem Ayçiçek; Karakılıç, Ersen; Tuna, Mazhar Müslüm; Arduç, Ayşe; Berker, Dilek; Güler, Serdar

2015-03-01

Idiopathic hypogonadotropic hypogonadism is a rare disorder. This study evaluated the effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with this disorder. Forty-three male patients aged 30 (range: 24-39 years) who were newly diagnosed with idiopathic hypogonadotropic hypogonadism and 20 age-, sex- and weight-matched controls (range: 26-39 years) were included in the study. Androgen replacement therapy was given according to the Algorithm of Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes (2010; Journal of Clinical Endocrinology and Metabolism, 95, 2536). The patients were assessed at a pretreatment visit and 3 and 6 months after the treatment. Inflammatory markers and lipid parameters were evaluated. Endothelial function was assessed with brachial flow-mediated dilation of a brachial artery and high-resolution ultrasonography of the carotid intima-media thickness. The carotid intima-media thickness (P hypogonadism compared to the control subjects at the pretreatment visit. There was a negative correlation between the total testosterone level and carotid intima-media thickness (r = -0·556, P = hypogonadism and that androgen replacement therapy significantly reduces atherosclerotic risk markers in these patients after 6 months. © 2014 John Wiley & Sons Ltd.

Osteoporosis prophylaxis in patients receiving chronic glucocorticoid therapy

International Nuclear Information System (INIS)

Ali, Mir Sadat; AlElq, Abdulmohsen H.; AlShafei, Badar A.; AbuJubarac, Mohammed A.; AlTurki, Haifa A.

2009-01-01

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, yet few patients receive proper measures to prevent its development. We retrospectively searched prescription records to determine if patients receiving oral prednisolone were receiving prophylaxis or treatment for osteopenia and osteoporosis. Patients who were prescribed greater or equal to 7.5 milligrams of prednisolone for 6 months or longer during a 6- month period were identified through the prescription monitoring system. Demographic and clinical data were extracted from the patient records, and dual energy x-ray absorptiometry (DEXA) scans were retrieved, when available. Use of oral calcium, vitamin D and anti-resorptives was recorded. One hundred males and 65 females were receiving oral prednisolone for a mean (SD) duration of 40.4 (29.9) months in males and 41.2 (36.4) months in females. Twenty-one females (12.7%) and 5 (3%) males had bone mineral density measured by DEXA. Of those, 10 (47.6%) females and 3 (50%) males were osteoporotic and 11(52.4%) females and 2 (40%) males were osteopenic. Calcium and vitamin D were prescribed to the majority of patients (60% to 80%), but none were prescribed antiresorptive/anabolic therapy. Patients in this study were neither investigated properly nor treated according to the minimum recommendations for the management of GIOP. Physician awareness about the prevention and treatment of GIOP should be a priority for the local health care system. (author)

Evolution of the androgen-induced male phenotype.

Science.gov (United States)

Fuxjager, Matthew J; Miles, Meredith C; Schlinger, Barney A

2018-01-01

The masculine reproductive phenotype varies significantly across vertebrates. As a result, biologists have long recognized that many of the mechanisms that support these phenotypes-particularly the androgenic system-is evolutionarily labile, and thus susceptible to the effects of selection for different traits. However, exactly how androgenic signaling systems vary in a way which results in dramatically different functional outputs, remain largely unclear. We explore this topic here by outlining four key-but non-mutually exclusive-hypotheses that propose how the mechanisms of androgenic signaling might change over time to potentiate the emergence of phenotypical variation in masculine behavior and physiology. We anchor this framework in a review of our own studies of a tropical bird called the golden-collared manakin (Manacus vitellinus), which has evolved an exaggerated acrobatic courtship display that is heavily androgen-dependent. The result is an example of how the cellular basis of androgenic action can be modified to support a unique reproductive repertoire. We end this review by highlighting a broad pathway forward to further pursue the intricate ways by which the mechanisms of hormone action evolve to support processes of adaptation and animal design.

Atmospheric Pressure Photoionization Tandem Mass Spectrometry of Androgens in Prostate Cancer

Science.gov (United States)

Lih, Fred Bjørn; Titus, Mark A.; Mohler, James L.; Tomer, Kenneth B.

2010-01-01

Androgen deprivation therapy is the most common treatment option for advanced prostate cancer. Almost all prostate cancers recur during androgen deprivation therapy, and new evidence suggests that androgen receptor activation persists despite castrate levels of circulating androgens. Quantitation of tissue levels of androgens is critical to understanding the mechanism of recurrence of prostate cancer during androgen deprivation therapy. A liquid chromatography atmospheric pressure photoionization tandem mass spectrometric method was developed for quantitation of tissue levels of androgens. Quantitation of the saturated keto-steroids dihydrotestosterone and 5-α-androstanedione required detection of a novel parent ion, [M + 15]+. The nature of this parent ion was explored and the method applied to prostate tissue and cell culture with comparison to results achieved using electrospray ionization. PMID:20560527

Myocardial infarction, androgen and the skin.

Science.gov (United States)

Halim, M M; Meyrick, G; Jeans, W D; Murphy, D; Burton, J L

1978-01-01

Various indices of masculinity were compared in 48 men who had recovered from myocardial infarction and in their age-matched controls. We found little evidence to support the idea that myocardial infarction is related to increased androgenic stimulation. The patients with myocardial infarction had no increase in plasma testosterone, muscle thickness, sebum excretion rate, maximal sweat secretion rate, male pattern alopecia or density of terminal body hair, but as a group they had a slight increase in skin and bone thickness compared with the controls.

Androgen receptor polyglutamine repeat length (AR-CAGn) modulates the effect of testosterone on androgen-associated somatic traits in Filipino young adult men.

Science.gov (United States)

Ryan, Calen P; Georgiev, Alexander V; McDade, Thomas W; Gettler, Lee T; Eisenberg, Dan T A; Rzhetskaya, Margarita; Agustin, Sonny S; Hayes, M Geoffrey; Kuzawa, Christopher W

2017-06-01

The androgen receptor (AR) mediates expression of androgen-associated somatic traits such as muscle mass and strength. Within the human AR is a highly variable glutamine short-tandem repeat (AR-CAGn), and CAG repeat number has been inversely correlated to AR transcriptional activity in vitro. However, evidence for an attenuating effect of long AR-CAGn on androgen-associated somatic traits has been inconsistent in human populations. One possible explanation for this lack of consistency is that the effect of AR-CAGn on AR bioactivity in target tissues likely varies in relation to circulating androgen levels. We tested whether relationships between AR-CAGn and several androgen-associated somatic traits (waist circumference, lean mass, arm muscle area, and grip strength) were modified by salivary (waking and pre-bed) and circulating (total) testosterone (T) levels in young adult males living in metropolitan Cebu, Philippines (n = 675). When men's waking T was low, they had a reduction in three out of four androgen-associated somatic traits with lengthening AR-CAGn (p AR-CAGn was associated with an increase in these same somatic traits. Our finding that longer AR-CAGn predicts greater androgen-associated trait expression among high-T men runs counter to in vitro work, but is generally consistent with the few prior studies to evaluate similar interactions in human populations. Collectively, these results raise questions about the applicability of findings derived from in vitro AR-CAGn studies to the receptor's role in maintaining androgen-associated somatic traits in human populations. © 2017 Wiley Periodicals, Inc.

Dehydroepiandrosterone substitution in female adrenal failure: no impact on endothelial function and cardiovascular parameters despite normalization of androgen status

DEFF Research Database (Denmark)

Christiansen, Jens Juel; Andersen, Niels Holmark; Sørensen, Keld E

2007-01-01

because of skin side effects and anxiety, respectively. All patients had low circulating androgens baseline and normal range androgens during DHEA treatment. We examined patients with noninvasive endothelial cell function, magnetic resonance imaging (MRI)-based cardiac output, echocardiography, ambulatory...... 24-h blood pressure and maximal oxygen consumption. RESULTS: DHEA treatment normalized androgen status to levels seen in healthy women. DHEA and placebo treatment had no effect on echocardiographic parameters of myocardial dimensions or systolic and diastolic function, noninvasive endothelial cell...... in vascular endothelium has been described and in vitro studies have shown involvement of DHEA in NO dependent pathways. AIM: To evaluate effects of DHEA substitution on cardiovascular parameters. DESIGN: Six months randomized, double-blind, placebo-controlled crossover study. Treatment consisted of DHEA 50...

Abhydrolase domain containing 2, an androgen target gene, promotes prostate cancer cell proliferation and migration.

Science.gov (United States)

Obinata, Daisuke; Takada, Shogo; Takayama, Ken-ichi; Urano, Tomohiko; Ito, Akiko; Ashikari, Daisaku; Fujiwara, Kyoko; Yamada, Yuta; Murata, Taro; Kumagai, Jinpei; Fujimura, Tetsuya; Ikeda, Kazuhiro; Horie-Inoue, Kuniko; Homma, Yukio; Takahashi, Satoru; Inoue, Satoshi

2016-04-01

The androgen receptor (AR) plays a key role in the development of prostate cancer. AR signalling mediates the expression of androgen-responsive genes, which are involved in prostate cancer development and progression. Our previous chromatin immunoprecipitation study showed that the region of abhydrolase domain containing 2 (ABHD2) includes a functional androgen receptor binding site. In this study, we demonstrated that ABHD2 is a novel androgen-responsive gene that is overexpressed in human prostate cancer tissues. The expression levels of ABHD2 in androgen-sensitive cells were evaluated by quantitative reverse transcription polymerase chain reaction and western-blot analyses. LNCaP and VCaP cells with ABHD2 overexpression or short interfering RNA (siRNA) knockdown were used for functional analyses. ABHD2 expression was examined in clinical samples of prostate cancer by immunohistochemistry. We showed that ABHD2 expression is increased by androgen in LNCaP and VCaP cells. This androgen-induced ABHD2 expression was diminished by bicalutamide. While stable expression of ABHD2 affected the enhancement of LNCaP cell proliferation and migration, siRNA-mediated ABHD2 knockdown suppressed cell proliferation and migration. In addition, the siRNA treatment significantly repressed the tumour growth derived from LNCaP cells in athymic mice. Immunohistochemical analysis of ABHD2 expression in tumour specimens showed a positive correlation of ABHD2 immunoreactivity with high Gleason score and pathological N stage. Moreover, patients with high immunoreactivity of ABHD2 showed low cancer-specific survival rates and a resistance to docetaxel-based chemotherapy. ABHD2 is a novel androgen-regulated gene that can promote prostate cancer growth and resistance to chemotherapy, and is a novel target for diagnosis and treatment of prostate cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Anabolic androgenic steroids reverse the beneficial effect of exercise on tendon biomechanics: an experimental study.

Science.gov (United States)

Tsitsilonis, Serafim; Chatzistergos, Panayiotis E; Panayiotis, Chatzistergos E; Mitousoudis, Athanasios S; Athanasios, Mitousoudis S; Kourkoulis, Stavros K; Stavros, Kourkoulis K; Vlachos, Ioannis S; Ioannis, Vlachos S; Agrogiannis, George; George, Agrogiannis; Fasseas, Konstantinos; Konstantinos, Fasseas; Perrea, Despina N; Despina, Perrea N; Zoubos, Aristides B; Aristides, Zoubos B

2014-06-01

The effect of anabolic androgenic steroids on tendons has not yet been fully elucidated. Aim of the present study was the evaluation of the impact of anabolic androgenic steroids on the biomechanical and histological characteristics of Achilles tendons. Twenty-four male Wistar rats were randomized into four groups with exercise and anabolic steroids (nandrolone decanoate) serving as variables. Protocol duration was 12 weeks. Following euthanasia, tendons' biomechanical properties were tested with the use of a modified clamping configuration. Histological examination with light and electron microscopy were also performed. In the group of anabolic steroids and exercise the lowest fracture stress values were observed, while in the exercise group the highest ones. Histological examination by light and electron microscopy revealed areas of collagen dysplasia and an increased epitendon in the groups receiving anabolic steroids and exercise. These findings suggest that anabolic androgenic steroids reverse the beneficial effect of exercise, thus resulting in inferior maximal stress values. Copyright © 2013 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

Intensity-Modulated Radiotherapy Reduces Gastrointestinal Toxicity in Patients Treated With Androgen Deprivation Therapy for Prostate Cancer

International Nuclear Information System (INIS)

Sharma, Navesh K.; Li Tianyu; Chen, David Y.; Pollack, Alan; Horwitz, Eric M.; Buyyounouski, Mark K.

2011-01-01

Purpose: Androgen deprivation therapy (AD) has been shown to increase late Grade 2 or greater rectal toxicity when used concurrently with three-dimensional conformal radiotherapy (3D-CRT). Intensity-modulated radiotherapy (IMRT) has the potential to reduce toxicity by limiting the radiation dose received by the bowel and bladder. The present study compared the genitourinary and gastrointestinal (GI) toxicity in men treated with 3D-CRT+AD vs. IMRT+AD. Methods and Materials: Between July 1992 and July 2004, 293 men underwent 3D-CRT (n = 170) or IMRT (n = 123) with concurrent AD (<6 months, n = 123; ≥6 months, n = 170). The median radiation dose was 76 Gy for 3D-CRT (International Commission on Radiation Units and Measurements) and 76 Gy for IMRT (95% to the planning target volume). Toxicity was assessed by a patient symptom questionnaire that was completed at each visit and recorded using a Fox Chase Modified Late Effects Normal Tissue Task radiation morbidity scale. Results: The mean follow-up was 86 months (standard deviation, 29.3) for the 3D-CRT group and 40 months (standard deviation, 9.7) for the IMRT group. Acute GI toxicity (odds ratio, 4; 95% confidence interval, 1.6-11.7; p = .005) was significantly greater with 3D-CRT than with IMRT and was independent of the AD duration (i.e., <6 vs. ≥6 months). The interval to the development of late GI toxicity was significantly longer in the IMRT group. The 5-year Kaplan-Meier estimate for Grade 2 or greater GI toxicity was 20% for 3D-CRT and 8% for IMRT (p = .01). On multivariate analysis, Grade 2 or greater late GI toxicity (hazard ratio, 2.1; 95% confidence interval, 1.1-4.3; p = .04) was more prevalent in the 3D-CRT patients. Conclusion: Compared with 3D-CRT, IMRT significantly decreased the acute and late GI toxicity in patients treated with AD.

The long-term outcome of boys with partial androgen insensitivity syndrome and a mutation in the androgen receptor gene

NARCIS (Netherlands)

Lucas-Herald, A.; S. Bertelloni (Silvano); A. Juul (Anders); J. Bryce (Jillian); Jiang, J.; M. Rodie (Martina); R. Sinnott (Richard); Boroujerdi, M.; Lindhardt Johansen, M.; O. Hiort (Olaf); P-M. Holterhus (Paul-Martin); M.L. Cools (Martine); Guaragna-Filho, G.; Guerra-Junior, G.; N. Weintrob (Naomi); S.E. Hannema (Sabine); S.L.S. Drop (Stenvert); T. Guran (Tulay); F. Darendeliler (Feyza); A. Nordenström (Anna); I.A. Hughes (Ieuan A.); Acerini, C.; Tadokoro-Cuccaro, R.; S.F. Ahmed (Faisal)

2016-01-01

textabstractBackground: In boys with suspected partial androgen insensitivity syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the androgen receptor gene (AR) is lacking. Objective: To assess the clinical characteristics and long-term

To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

International Nuclear Information System (INIS)

Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda; Jia, William; Rennie, Paul S.

2011-01-01

Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge

To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

Energy Technology Data Exchange (ETDEWEB)

Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Jia, William [Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Rennie, Paul S., E-mail: prennie@interchange.ubc.ca [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada)

2011-03-24

Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge.

To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

Directory of Open Access Journals (Sweden)

Paul S. Rennie

2011-03-01

Full Text Available Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i the PI3K/Akt pathway, (ii receptor tyrosine kinases, (iii the p38 MAPK pathway, and (iv the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge.

Radiotherapy and local hyperthermia plus androgen suppression in locally advanced prostate cancer

International Nuclear Information System (INIS)

Maluta, S.; Marciai, N.; Gabbani, M.; Palazzi, M.; Dall'Oglio, S.; Grandinetti, A.

2005-01-01

Full text: In advanced prostatic cancer, hyperthermia may be useful in order to enhance irradiation efficacy so to avoid delivering of too high dose of radiotherapy which increases acute and late sequelae. A multi-centric phase II study is warranted to give hyperthermia a level 3 evidence in prostate cancer treatment. A randomized phase III study to demonstrate efficacy of hyperthermia is not available because of the optimal results obtained by using radiotherapy combined with androgen suppression. To evaluate hyperthermia gain, LHT should be combined with radiotherapy alone in patients refusing androgen suppression or affected by hormone refractory prostate carcinoma (HRPC). Patients with HRPC have multiple possibilities of treatment improving performance status and median survival, as chemotherapy regimens, and new agents. All these treatments modalities need to be confirmed by phase III trials. Also hyperthermia may be considered among these promising approaches. (author)

The prognostic value of expression of HIF1α, EGFR and VEGF-A, in localized prostate cancer for intermediate- and high-risk patients treated with radiation therapy with or without androgen deprivation therapy

Directory of Open Access Journals (Sweden)

Weber Damien C

2012-04-01

Full Text Available Abstract Purpose Androgens stimulate the production of hypoxia-inducible factor (HIF1α and ultimately vascular endothelial growth factor (VEGF-A. Additionally, epithelial growth factor (EGF mediates HIF1α production. Carbonic anhydrase IX (CAIX expression is associated with tumor cell hypoxia in a variety of malignancies. This study assesses the prognostic relation between HIF1α, VEGF-A, EGF Receptor and CAIX expression by immunochemistry in diagnostic samples of patients with intermediate- and high-risk localized prostate cancer treated with radiation therapy, with or without androgen deprivation therapy (ADT. Materials and methods Between 1994 and 2004, 103 prostate cancer patients (mean age, 68.7 ± 6.2, with prostate cancer (mean PSA, 13.3 ± 3.7, were treated with radiation therapy (RT, median dose, 74 Gy. Fifty seven (55.3% patients received ADT (median duration, 6 months; range, 0 – 24. Median follow-up was 97.6 months (range, 5.9 – 206.8. Results Higher EGFR expression was significantly (p = 0.04 correlated with higher Gleason scores. On univariate analysis, HIF1α nuclear expression was a significant (p = 0.02 prognostic factor for biological progression-free survival (bPFS. A trend towards significance (p = 0.05 was observed with EGFR expression and bPFS. On multivariate analysis, low HIF1α nuclear (p = 0.01 and high EGFR (p = 0.04 expression remained significant adverse prognostic factors. Conclusions Our study suggests that high nuclear expression of HIF1α and low EGFR expression in diagnostic biopsies of prostate cancer patients treated with RT ± ADT is associated with a good prognosis.

Long-lasting masculinizing effects of postnatal androgens on myelin governed by the brain androgen receptor

Science.gov (United States)

Abi Ghanem, Charly; Degerny, Cindy; Hussain, Rashad; Liere, Philippe; Pianos, Antoine; Tourpin, Sophie; Habert, René; Schumacher, Michael

2017-01-01

The oligodendrocyte density is greater and myelin sheaths are thicker in the adult male mouse brain when compared with females. Here, we show that these sex differences emerge during the first 10 postnatal days, precisely at a stage when a late wave of oligodendrocyte progenitor cells arises and starts differentiating. Androgen levels, analyzed by gas chromatography/tandem-mass spectrometry, were higher in males than in females during this period. Treating male pups with flutamide, an androgen receptor (AR) antagonist, or female pups with 5α-dihydrotestosterone (5α-DHT), revealed the importance of postnatal androgens in masculinizing myelin and their persistent effect into adulthood. A key role of the brain AR in establishing the sexual phenotype of myelin was demonstrated by its conditional deletion. Our results uncover a new persistent effect of postnatal AR signaling, with implications for neurodevelopmental disorders and sex differences in multiple sclerosis. PMID:29107990

Critical androgen-sensitive periods of rat penis and clitoris development

OpenAIRE

Welsh, M.; Macleod, D. J.; Walker, M.; Smith, L. B.; Sharpe, R. M.

2010-01-01

Androgen control of penis development/growth is unclear. In rats, androgen action in a foetal 'masculinisation programming window' (MPW; e15.5-e18.5)' predetermines penile length and hypospadias occurrence. This has implications for humans (e.g. micropenis). Our studies aimed to establish in rats when androgen action/administration affects development/growth of the penis and if deficits in MPW androgen action were rescuable postnatally. Thus, pregnant rats were treated with flutamide during t...

Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer.

Science.gov (United States)

Takahashi, Satoru; Uemura, Hiroji; Seeni, Azman; Tang, Mingxi; Komiya, Masami; Long, Ne; Ishiguro, Hitoshi; Kubota, Yoshinobu; Shirai, Tomoyuki

2012-10-01

With the limited strategies for curative treatment of castration-resistant prostate cancer (CRPC), public interest has focused on the potential prevention of prostate cancer. Recent studies have demonstrated that an angiotensin II receptor blocker (ARB) has the potential to decrease serum prostate-specific antigen (PSA) level and improve performance status in CRPC patients. These facts prompted us to investigate the direct effects of ARBs on prostate cancer growth and progression. Transgenic rat for adenocarcinoma of prostate (TRAP) model established in our laboratory was used. TRAP rats of 3 weeks of age received ARB (telmisartan or candesartan) at the concentration of 2 or 10 mg/kg/day in drinking water for 12 weeks. In vitro analyses for cell growth, ubiquitylation or reporter gene assay were performed using LNCaP cells. We found that both telmisartan and candesartan attenuated prostate carcinogenesis in TRAP rats by augmentation of apoptosis resulting from activation of caspases, inactivation of p38 MAPK and down-regulation of the androgen receptor (AR). Further, microarray analysis demonstrated up-regulation of estrogen receptor β (ERβ) by ARB treatment. In both parental and androgen-independent LNCaP cells, ARB inhibited both cell growth and AR-mediated transcriptional activity. ARB also exerted a mild additional effect on AR-mediated transcriptional activation by the ERβ up-regulation. An intervention study revealed that PSA progression was prolonged in prostate cancer patients given an ARB compared with placebo control. These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer. Copyright © 2012 Wiley Periodicals, Inc.

Androgen receptor and histone lysine demethylases in ovine placenta.

Directory of Open Access Journals (Sweden)

Ellane R Cleys

Full Text Available Sex steroid hormones regulate developmental programming in many tissues, including programming gene expression during prenatal development. While estradiol is known to regulate placentation, little is known about the role of testosterone and androgen signaling in placental development despite the fact that testosterone rises in maternal circulation during pregnancy and in placenta-induced pregnancy disorders. We investigated the role of testosterone in placental gene expression, and focused on androgen receptor (AR. Prenatal androgenization decreased global DNA methylation in gestational day 90 placentomes, and increased placental expression of AR as well as genes involved in epigenetic regulation, angiogenesis, and growth. As AR complexes with histone lysine demethylases (KDMs to regulate AR target genes in human cancers, we also investigated if the same mechanism is present in the ovine placenta. AR co-immunoprecipitated with KDM1A and KDM4D in sheep placentomes, and AR-KDM1A complexes were recruited to a half-site for androgen response element (ARE in the promoter region of VEGFA. Androgenized ewes also had increased cotyledonary VEGFA. Finally, in human first trimester placental samples KDM1A and KDM4D immunolocalized to the syncytiotrophoblast, with nuclear KDM1A and KDM4D immunostaining also present in the villous stroma. In conclusion, placental androgen signaling, possibly through AR-KDM complex recruitment to AREs, regulates placental VEGFA expression. AR and KDMs are also present in first trimester human placenta. Androgens appear to be an important regulator of trophoblast differentiation and placental development, and aberrant androgen signaling may contribute to the development of placental disorders.

Androgen receptor mutations associated with androgen insensitivity syndrome: a high content analysis approach leading to personalized medicine.

Directory of Open Access Journals (Sweden)

Adam T Szafran

2009-12-01

Full Text Available Androgen insensitivity syndrome (AIS is a rare disease associated with inactivating mutations of AR that disrupt male sexual differentiation, and cause a spectrum of phenotypic abnormalities having as a common denominator loss of reproductive viability. No established treatment exists for these conditions, however there are sporadic reports of patients (or recapitulated mutations in cell lines that respond to administration of supraphysiologic doses (or pulses of testosterone or synthetic ligands. Here, we utilize a novel high content analysis (HCA approach to study AR function at the single cell level in genital skin fibroblasts (GSF. We discuss in detail findings in GSF from three historical patients with AIS, which include identification of novel mechanisms of AR malfunction, and the potential ability to utilize HCA for personalized treatment of patients affected by this condition.

8. Prevalence of Epistaxis among Patients Receiving ...

African Journals Online (AJOL)

user

The aim of this study was thus to determine the prevalence, aetiology and treatment modalities of epistaxis among patients receiving otorhinolaryngology services at MNH and MOI. Materials and Methods: A cross-sectional, hospital based study was done to 427 patients at Muhimbili. National Hospital (MNH) and Muhimbili.

The Role of Androgen Excess in Metabolic Dysfunction in Women : Androgen Excess and Female Metabolic Dysfunction.

Science.gov (United States)

Escobar-Morreale, Héctor F

2017-01-01

Polycystic ovary syndrome (PCOS) is characterized by the association of androgen excess with chronic oligoovulation and/or polycystic ovarian morphology, yet metabolic disorders and classic and nonclassic cardiovascular risk factors cluster in these women from very early in life. This chapter focuses on the mechanisms underlying the association of PCOS with metabolic dysfunction, focusing on the role of androgen excess on the development of visceral adiposity and adipose tissue dysfunction.

Unraveling the Complexities of Androgen Receptor Signaling in Prostate Cancer Cells

OpenAIRE

Heemers, Hannelore V.; Tindall, Donald J.

2009-01-01

Androgen signaling is critical for proliferation of prostate cancer cells but cannot be fully inhibited by current androgen deprivation therapies. A study by Xu et al. in this issue of Cancer Cell provides insights into the complexities of androgen signaling in prostate cancer and suggests avenues to target a subset of androgen-sensitive genes.

Androgen deficiency in male patients diagnosed with ANCA-associated vasculitis: a cause of fatigue and reduced health-related quality of life?

OpenAIRE

Tuin, Janneke; Sanders, Jan-Stephan F; Buhl, Birgit M; van Beek, André P; Stegeman, Coen A

2013-01-01

Introduction: Low testosterone levels in men are associated with fatigue, limited physical performance and reduced health-related quality of life (HRQOL); however, this relationship has never been assessed in patients with anti-neutrophil cytoplasmic antibodies (ANCA) -associated vasculitides (AAV). The aim of this study was to assess the prevalence of androgen deficiency and to investigate the role of testosterone in fatigue, limited physical condition and reduced HRQOL in men with AAV. Meth...

Long-term side-effects of intermittent androgen suppression therapy in prostate cancer: results of a phase II study.

Science.gov (United States)

Malone, Shawn; Perry, Gad; Segal, Roanne; Dahrouge, Simone; Crook, Juanita

2005-09-01

To assess the feasibility and tolerability of intermittent androgen suppression therapy (IAS) in prostate cancer. Patients with recurrent or metastic prostate cancer received cyclical periods of treatment with leuprolide acetate and nilutamide for 8 months, and rest periods. Cycles were repeated at progression until the treatment failed to achieve normal prostate-specific antigen (PSA) levels. Patients were followed with PSA level, testosterone level, haemoglobin level, weight and bone mineral density evaluations. The median time to treatment failure, recovery from anaemia, or normalization of testosterone level was estimated by the Kaplan-Meier method. In all, 95 patients received 245 cycles; the median duration of rest periods was 8 months and median time to treatment failure 47 months. Testosterone recovery during rest periods was documented in 117 (61%) of cycles. Anaemia was mild and reported in 33%, 44% and 67% of cycles 1, 2 and 3, respectively. Sexual function recovered during the rest periods in 47% of cycles. There was no significant overall change in body mass index at the end of the treatment period. Osteoporosis was documented in at least one site evaluated in 41 patients (37%). IAS has the potential to reduce side-effects, including recovery of haemoglobin level, return of sexual function and absence of weight gain at the end of the study period.

Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer.

Science.gov (United States)

Wilcox, Shea W; Aherne, Noel J; Benjamin, Linus C; Wu, Bosco; de Campos Silva, Thomaz; McLachlan, Craig S; McKay, Michael J; Last, Andrew J; Shakespeare, Thomas P

2014-01-01

Dose-escalated (DE) radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS) in several studies. In the same group of patients, androgen deprivation therapy (ADT) has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT) with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT) and ADT. Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2.1% and 3.4%, respectively. No grade 3 or 4 late toxicities were reported. Pretreatment prostate specific antigen (P=0.001) and Gleason score (P=0.03) were significant in predicting biochemical failure on multivariate analysis. There is a high probability of tumor control with DE IG-IMRT combined with androgen deprivation, and this is a technique with a low probability of significant late toxicity. Our long term results corroborate the safety and efficacy of treating with IG-IMRT to high doses and compares favorably with published series for

Role of Androgen Receptor in Growth of Androgen Independent Prostate Cancer

National Research Council Canada - National Science Library

Chen, Charlie

2003-01-01

...) overexpression is the only consistent change in the progression of prostate cancer. In the last grand period, I confirmed by western blot analysis that androgen receptor protein is higher in HR than HS tumors...

Neoadjuvant androgen deprivation plus prostatectomy for stage T3 disease: lack of PSA-based benefit even among patients with negative lymphadenectomy

Energy Technology Data Exchange (ETDEWEB)

Hyslop, T; Corn, B; Werner-Wasik, M; Gomella, L

1995-07-01

Objective: Urologists have attempted to treat stage T3 prostate cancer by neoadjuvant total androgen deprivation (TAD) and prostatectomy. This approach has been disappointing because of the inability of ultrasonography to predict pathological disease status and frequent upstaging due to nodal positivity. Moreover, no reports give PSA-based outcome data among patients treated with TAD and prostatectomy. We therefore instituted a pilot study for T3 disease based on non-invasive staging (endorectal coil MRI), mandatory negative laparoscopic nodal dissections prior to hormonal manipulation, and prostatectomy followed by pathological and PSA-based outcome determinations. Materials and Methods: Twenty-one patients had negative laparoscopic lymphadenectomy followed by 4 months of neoadjuvant hormonal treatment (Lupron, Flutamide) prior to radical prostatectomy. Endorectal coil MRI was performed at the time of diagnosis and following hormonal treatment. Serum PSA was determined at 3 month intervals. Prostatectomy specimens were evaluated by 3 mm whole mount step sections. Results: Median age was 63 (range: 51-68). Karnofsky performance status was 90-100 in all patients. The median number of nodes sampled was 10 (range: 2-60). Prior to prostatectomy, downsizing was observed by MRI in 57% and biochemical response was documented in all patients. However, pathological downstaging to a lower state ({<=}T2c) was achieved in only 48%. The actuarial 3 year freedom from biochemical relapse was only 24%. Conclusion: Neither serum PSA response nor MRI downsizing predicted pathological disease status after pre-operative androgen deprivation. Even in the setting of pathologically negative lymph nodes, TAD decreased the pathological stage of disease in the minority of patients. The present approach appeared to offer no advantage when compared with PSA-based benchmarks achieved with conformal irradiation (Urology 45: 484, 1995) or TAD followed by external beam treatment (IJROBP 27: 246

Neoadjuvant androgen deprivation plus prostatectomy for stage T3 disease: lack of PSA-based benefit even among patients with negative lymphadenectomy

International Nuclear Information System (INIS)

Hyslop, T.; Corn, B.; Werner-Wasik, M.; Gomella, L.

1995-01-01

Objective: Urologists have attempted to treat stage T3 prostate cancer by neoadjuvant total androgen deprivation (TAD) and prostatectomy. This approach has been disappointing because of the inability of ultrasonography to predict pathological disease status and frequent upstaging due to nodal positivity. Moreover, no reports give PSA-based outcome data among patients treated with TAD and prostatectomy. We therefore instituted a pilot study for T3 disease based on non-invasive staging (endorectal coil MRI), mandatory negative laparoscopic nodal dissections prior to hormonal manipulation, and prostatectomy followed by pathological and PSA-based outcome determinations. Materials and Methods: Twenty-one patients had negative laparoscopic lymphadenectomy followed by 4 months of neoadjuvant hormonal treatment (Lupron, Flutamide) prior to radical prostatectomy. Endorectal coil MRI was performed at the time of diagnosis and following hormonal treatment. Serum PSA was determined at 3 month intervals. Prostatectomy specimens were evaluated by 3 mm whole mount step sections. Results: Median age was 63 (range: 51-68). Karnofsky performance status was 90-100 in all patients. The median number of nodes sampled was 10 (range: 2-60). Prior to prostatectomy, downsizing was observed by MRI in 57% and biochemical response was documented in all patients. However, pathological downstaging to a lower state (≤T2c) was achieved in only 48%. The actuarial 3 year freedom from biochemical relapse was only 24%. Conclusion: Neither serum PSA response nor MRI downsizing predicted pathological disease status after pre-operative androgen deprivation. Even in the setting of pathologically negative lymph nodes, TAD decreased the pathological stage of disease in the minority of patients. The present approach appeared to offer no advantage when compared with PSA-based benchmarks achieved with conformal irradiation (Urology 45: 484, 1995) or TAD followed by external beam treatment (IJROBP 27: 246

Risk factors for bone loss with prostate cancer in Korean men not receiving androgen deprivation therapy

Directory of Open Access Journals (Sweden)

Sun-Ouck Kim

2009-04-01

Full Text Available PURPOSE: Preexisting bone loss in men with prostate cancer is an important issue due to the accelerated bone loss during androgen deprivation therapy (ADT. In addition, a high prostate-specific antigen (PSA level has been reported to be related to bone metabolism. This study assessed the factors associated with osteoporosis in Korean men with non-metastatic prostate cancer before undergoing ADT. MATERIAL AND METHODS: The study enrolled patients admitted for a prostate biopsy because of a high PSA or palpable nodule on a digital rectal examination. We divided the patients (n = 172 according to the results of the biopsy: group I, non-metastatic prostate cancer (n = 42 and group II, benign prostatic hypertrophy (BPH; n = 130. The lumbar bone mineral density (BMD was evaluated using quantitative computed tomography. The demographic, health status, lifestyle, body mass index (BMI, serum testosterone concentration, and disease variables in prostate cancer (Gleason score, clinical stage, and PSA were analyzed prospectively to determine their effect on the BMD. RESULTS: The estimated mean T-score was higher in group I than in group II (-1.96 ± 3.35 vs. -2.66 ± 3.20, but without statistic significance (p = 0.235. The significant factors correlated with BMD in group I were a high serum PSA (ß = -0.346, p = 0.010 and low BMI (ß = 0.345, p = 0.014 in the multiple linear regression model. Also old age (r = -0.481, p = 0.001, a high serum PSA (r = -0.571, p < 0.001, low BMI (r = 0.598, p < 0.001, and a high Gleason’s score (r = -0.319, p = 0.040 were the factors related to BMD in the correlation. The significant factors correlated with BMD in group II were old age (ß = -0.324, p = 0.001 and BMI (ß = 0.143, p = 0.014 in the multiple linear regression model. CONCLUSIONS: The risk factors for osteoporosis in men with prostate cancer include a low BMI, and elevated serum PSA. Monitoring BMD from the outset of ADT is a logical first step in the clinical

Hormonal response recovery after long-term androgen deprivation therapy in patients with prostate cancer.

Science.gov (United States)

Planas, Jacques; Celma, Ana; Placer, José; Cuadras, Mercè; Regis, Lucas; Gasanz, Carlos; Trilla, Enrique; Salvador, Carlos; Lorente, David; Morote, Juan

2016-12-01

The aim of this study was to evaluate hormonal recovery after cessation of androgen deprivation therapy (ADT) in a group of elderly prostate cancer patients. Forty patients with locally advanced or metastatic prostate cancer, with a mean age of 71.5 years [95% confidence interval (CI) 69.1-73.9], were treated with ADT for a mean duration of 74.6 months (95% CI 59.7-89.5 months). Mean follow-up time after ADT cessation was 36.5 months (95% CI 30.6-42.3 months). Serum testosterone and luteinizing hormone (LH) were determined at 6 month intervals after ADT cessation. After 18 months of follow-up, all patients had recovered normal LH levels, while 38% of patients still presented castration levels of testosterone (50 ng/dl). Neither age at start of ADT nor clinical stage reached statistical significance. Only time under ADT was correlated with testosterone recovery (p = .031). Kaplan-Meier curves were obtained. Mean time for testosterone recovery was 14.5 months (95% CI 6.5-22.6 months) in patients treated with ADT for less than 60 months compared to 29.3 months (95% CI 19.6-39.1 months) in patients treated with ADT for more than 60 months (log-rank p = .029). Age did not correlate with testosterone recovery in a group of elderly prostate cancer patients in whom ADT was stopped. Testosterone recovery after ADT cessation was significantly correlated with time under ADT treatment. Significant implications related to economic aspects of the dosage schedule may be considered.

Economic Evaluation of a Patient-Directed Music Intervention for ICU Patients Receiving Mechanical Ventilatory Support.

Science.gov (United States)

Chlan, Linda L; Heiderscheit, Annette; Skaar, Debra J; Neidecker, Marjorie V

2018-05-04

Music intervention has been shown to reduce anxiety and sedative exposure among mechanically ventilated patients. Whether music intervention reduces ICU costs is not known. The aim of this study was to examine ICU costs for patients receiving a patient-directed music intervention compared with patients who received usual ICU care. A cost-effectiveness analysis from the hospital perspective was conducted to determine if patient-directed music intervention was cost-effective in improving patient-reported anxiety. Cost savings were also evaluated. One-way and probabilistic sensitivity analyses determined the influence of input variation on the cost-effectiveness. Midwestern ICUs. Adult ICU patients from a parent clinical trial receiving mechanical ventilatory support. Patients receiving the experimental patient-directed music intervention received a MP3 player, noise-canceling headphones, and music tailored to individual preferences by a music therapist. The base case cost-effectiveness analysis estimated patient-directed music intervention reduced anxiety by 19 points on the Visual Analogue Scale-Anxiety with a reduction in cost of $2,322/patient compared with usual ICU care, resulting in patient-directed music dominance. The probabilistic cost-effectiveness analysis found that average patient-directed music intervention costs were $2,155 less than usual ICU care and projected that cost saving is achieved in 70% of 1,000 iterations. Based on break-even analyses, cost saving is achieved if the per-patient cost of patient-directed music intervention remains below $2,651, a value eight times the base case of $329. Patient-directed music intervention is cost-effective for reducing anxiety in mechanically ventilated ICU patients.

MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease.

Science.gov (United States)

Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke; O'Reilly, Michael W

2017-09-01

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. © 2017 The authors.

Associations between statin use and progression in men with prostate cancer treated with primary androgen deprivation therapy

DEFF Research Database (Denmark)

Mikkelsen, Marta Kramer; Thomsen, Frederik Birkebæk; Berg, Kasper Drimer

2017-01-01

between statin use and risk of progression, HR 0.98 (95% CI: 0.72-1.32). In competing risk analyses the 5-year cumulative incidence of progression was 55% (95% CI: 46-64%) for statin users and 62% (95% CI: 57-67%) for non-statin users, p = 0.11. CONCLUSION: In the current study, statin use at time of PCa......INTRODUCTION: In several observational studies, statin use has been associated with reduced risk of progression and mortality in men with prostate cancer (PCa). The study aim was to investigate the association between statin use at time of PCa diagnosis and time to PCa progression in men...... with advanced or metastatic PCa receiving androgen deprivation therapy (ADT) as primary treatment. PATIENTS AND METHODS: The study population consisted of all men receiving ADT as primary therapy at two Danish Urological Departments in 2007-2013. The primary outcome was time to progression defined as castration...

Targets to treat androgen excess in polycystic ovary syndrome.

Science.gov (United States)

Luque-Ramírez, Manuel; Escobar-Morreale, Héctor Francisco

2015-01-01

The polycystic ovary syndrome (PCOS) is a common androgen disorder in reproductive-aged women. Excessive biosynthesis and secretion of androgens by steroidogenic tissues is its central pathogenetic mechanism. The authors review the potential targets and new drugs to treat androgen excess in PCOS. Besides our lab's experience, a systematic search (MEDLINE, Cochrane library, ClinicalTriasl.gov, EU Clinical Trials Register and hand-searching) regarding observational studies, randomized clinical trials, systematic reviews, meta-analyses and patents about this topic was performed. PCOS has a heterogeneous clinical presentation. It is unlikely that a single drug would cover all its possible manifestations. Available treatments for androgen excess are not free of side effects that are of particular concern in these women who suffer from cardiometabolic risk even without treatment. A precise characterization of the source of androgen excess must tailor antiandrogenic management in each woman, avoiding undesirable side effects.

Implant R100 Predicts Rectal Bleeding in Prostate Cancer Patients Treated with IG-IMRT to 45 Gy and Pd-103 Implant

OpenAIRE

Matthew Packard; Vladimir Valakh; Russell Fuhrer

2014-01-01

Purpose. To define factors associated with rectal bleeding in patients treated with IG-IMRT followed by Pd-103 seed implant. Methods and Materials. We retrospectively reviewed 61 prostate adenocarcinoma patients from 2002 to 2008. The majority (85.2%) were of NCCN intermediate risk category. All received IG-IMRT to the prostate and seminal vesicles followed by Pd-103 implant delivering a mean D90 of 100.7 Gy. Six patients received 45 Gy to the pelvic nodes and 10 received androgen deprivation...

An Update on Plant Derived Anti-Androgens

Science.gov (United States)

Grant, Paul; Ramasamy, Shamin

2012-01-01

Anti-androgens are an assorted group of drugs and compounds that reduce the levels or activity of androgen hormones within the human body. Disease states in which this is relevant include polycystic ovarian syndrome, hirsutism, acne, benign prostatic hyperplasia, and endocrine related cancers such as carcinoma of the prostate. We provide an overview and discussion of the use of anti-androgen medications in clinical practice and explore the increasing recognition of the benefits of plant-derived anti-androgens, for example, spearmint tea in the management of PCOS, for which some evidence about efficacy is beginning to emerge. Other agents covered include red reishi, which has been shown to reduce levels 5-alpha reductase, the enzyme that facilitates conversion of testosterone to dihydrotestosterone (DHT); licorice, which has phytoestrogen effects and reduces testosterone levels; Chinese peony, which promotes the aromatization of testosterone into estrogen; green tea, which contains epigallocatechins and also inhibits 5-alpha reductase, thereby reducing the conversion of normal testosterone into the more potent DHT; black cohosh, which has been shown to kill both androgenresponsive and non-responsive human prostate cancer cells; chaste tree, which has a reduces prolactin from the anterior pituitary; and saw palmetto extract, which is used as an anti-androgen although it shown no difference in comparison to placebo in clinical trials. PMID:23843810

Low-level laser therapy for the treatment of androgenic alopecia: a review.

Science.gov (United States)

Darwin, Evan; Heyes, Alexandra; Hirt, Penelope A; Wikramanayake, Tongyu Cao; Jimenez, Joaquin J

2018-02-01

There are many new low-level laser technologies that have been released commercially that claim to support hair regrowth. In this paper, we will examine the clinical trials to determine whether the body of evidence supports the use of low-level laser therapy (LLLT) to treat androgenic alopecia (AGA). A literature search was conducted through Pubmed, Embase, and Clinicaltrials.gov for clinical trials using LLLT to treat AGA. Thirteen clinical trials were assessed. Review articles were not included. Ten of 11 trials demonstrated significant improvement of androgenic alopecia in comparison to baseline or controls when treated with LLLT. In the remaining study, improvement in hair counts and hair diameter was recorded, but did not reach statistical significance. Two trials did not include statistical analysis, but showed marked improvement by hair count or by photographic evidence. Two trials showed efficacy for LLLT in combination with topical minoxidil. One trial showed efficacy when accompanying finasteride treatment. LLLT appears to be a safe, alternative treatment for patients with androgenic alopecia. Clinical trials have indicated efficacy for androgenic alopecia in both men and women. It may be used independently or as an adjuvant of minoxidil or finasteride. More research needs to be undertaken to determine the optimal power and wavelength to use in LLLT as well as LLLT's mechanism of action.

Effects of prasterone on bone mineral density in women with active systemic lupus erythematosus receiving chronic glucocorticoid therapy.

Science.gov (United States)

Sánchez-Guerrero, Jorge; Fragoso-Loyo, Hilda E; Neuwelt, C Michael; Wallace, Daniel J; Ginzler, Ellen M; Sherrer, Yvonne R S; McIlwain, Harris H; Freeman, Pamela G; Aranow, Cynthia; Petri, Michelle A; Deodhar, Atul A; Blanton, Ellen; Manzi, Susan; Kavanaugh, Arthur; Lisse, Jeffrey R; Ramsey-Goldman, Rosalind; McKay, James D; Kivitz, Alan J; Mease, Philip J; Winkler, Anne E; Kahl, Leslie E; Lee, Albert H; Furie, Richard A; Strand, C Vibeke; Lou, Lillian; Ahmed, Mumtaz; Quarles, Betty; Schwartz, Kenneth E

2008-08-01

To assess prevention of bone mineral density (BMD) loss and durability of the response during treatment with prasterone in women with systemic lupus erythematosus (SLE) receiving chronic glucocorticoids. 155 patients with SLE received 200 mg/day prasterone or placebo for 6 months in a double-blind phase. Subsequently, 114 patients were re-randomized to receive 200 or 100 mg/day prasterone for 12 months in an open-label phase. Primary efficacy endpoints were changes in BMD at the lumbar spine (L-spine) from baseline to Month 6 and maintenance of BMD from Month 6 to 18 for patients who received prasterone during the double-blind phase. In the double-blind phase, there was a trend for a small gain in BMD at the L-spine for patients who received 200 mg/day prasterone for 6 months versus a loss in the placebo group (mean +/- SD, 0.003 +/- 0.035 vs -0.005 +/- 0.053 g/cm(2), respectively; p = 0.293 between groups). In the open-label phase, there was dose-dependent increase in BMD at the L-spine at Month 18 between patients who received 200 versus 100 mg/day prasterone (p = 0.021). For patients who received 200 mg/day prasterone for 18 months, the L-spine BMD gain was 1.083 +/- 0.512% (p = 0.042). There was no overall change in BMD at the total hip over 18 months with 200 mg/day prasterone treatment. The safety profile reflected the weak androgenic properties of prasterone. This study suggests prasterone 200 mg/day may offer mild protection against bone loss in women with SLE receiving glucocorticoids. (ClinicalTrials.gov Identifiers NCT00053560 and NCT00082511).

Anxiety and depression in patients receiving radiotherapy. Prospective study

International Nuclear Information System (INIS)

Chaturvedi, S.K.; Chandra, P.S.; Channabasavanna, S.M.; Anantha, N.; Reddy, B.K.M.; Sharma, S.

1994-01-01

The objective of this study was to detect the prevalence of anxiety and depressive disorders using the Hospital Anxiety and Depression Scale (HADS) prospectively in patients receiving Radiotherapy (RT) during and after treatment. 140 consecutive cancer patients referred for radiotherapy and their care givers were included. All patients were administered the Hospital Anxiety and Depression Scale (HADS) conducted at intake, just before starting RT, after finishing the course of RT, and at 3-4 months follow-up. Anxiety and depression are detected frequently in patients receiving RT both prior to treatment and later during follow-up

Prostate Cancer Metastases to Bone: Role of High Bone Turnover Induced by Androgen Deprivation

National Research Council Canada - National Science Library

Padalecki, Susan

2002-01-01

.... Treatment with androgen deprivation therapy leads to an increase in bone turnover as indicated by the loss of bone mineral density and the increase in markers of bone turnover in patients on treatment...

Comparison of Alternative Androgen Receptor-axis-targeted Agent (ARATA) and Docetaxel as Second-line Therapy for Patients With Metastatic Castration-resistant Prostate Cancer With Progression After Initial ARATA in Real-world Clinical Practice in Japan.

Science.gov (United States)

Miyake, Hideaki; Sugiyama, Takayuki; Aki, Ryota; Matsushita, Yuto; Tamura, Keita; Motoyama, Daisuke; Ito, Toshiki; Otsuka, Atsushi

2018-06-01

The objective of the present study was to assess the oncologic outcomes of patients receiving second-line therapy against metastatic castration-resistant prostate cancer (mCRPC). The present study included 222 consecutive mCRPC patients with progression during initial androgen receptor-axis-targeted agent (ARATA) therapy with either abiraterone acetate (AA) or enzalutamide (Enz). Of these 222 patients, 108 subsequently received an alternative ARATA (AA-to-Enz, n = 49; Enz-to-AA, n = 59) and 114 received docetaxel (DTX; AA-to-DTX, n = 54; Enz-to-DTX, n = 60). The prostate-specific antigen (PSA) level in the 114 patients receiving DTX was significantly greater than that in the 108 patients receiving ARATA. However, no significant differences were found in the remaining parameters between the 2 groups. The PSA response rate, PSA progression-free survival (PFS), and overall survival (OS) during second-line therapy in the DTX group (n = 114) were significantly superior to those for the ARATA group (n = 108; PSA response rate, 42.1% vs. 21.3%; median PSA PFS, 7.2 vs. 4.2 months; median OS, 17.5 vs. 14.5 months). Similar trends were confirmed by comparing these outcomes among 4 therapy groups, with significant differences (PSA response rate, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX; PSA PFS, AA-to-Enz vs. Enz-to-AA, AA-to-Enz vs. AA-to-DTX, Enz-to-AA vs. AA-to-DTX, and Enz-to-AA vs. Enz-to-DTX; and OS, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX). Furthermore, the introduction of DTX was independently associated with improved PSA PFS, but not OS, on multivariate analysis. Favorable oncologic outcomes can be expected with DTX treatment, rather than with alternative ARATA, for mCRPC patients after failure of an initial ARATA. Copyright © 2017 Elsevier Inc. All rights reserved.

Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function.

Science.gov (United States)

Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao

2015-11-01

Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Umbilical KeyPort bilateral laparoscopic orchiectomy in patient with complete androgen insensitivity syndrome

Directory of Open Access Journals (Sweden)

Felipe P. Andrade

2012-10-01

Full Text Available MAIN FINDINGS: A 22-year-old woman with complete androgen insensitivity syndrome (CAIS presenting with primary amenorrhea and normal female external genitalia was referred for laparoscopic gonadectomy. She had been diagnosed several years earlier but was reluctant to undergo surgery. CASE HYPOTHESIS: Diagnosis of this X-linked recessive inherited syndrome characterizes by disturbance of virilization in males with an AR mutation, XY karyotipe, female genitalia and severely undescended testis with risk of malignization. The optimal time to orchidectomy is not settled; neither the real risk of malignancy in these patients. Early surgery impacts development of a complete female phenotype, with enlargement of the breasts. Based on modern diagnostic imaging using DCE-MRI and surgical technology with single port laparoscopic access we hypothesize that the optimum time for gonadectomy is not at the time of diagnosis, but once feminization has completed. PROMISING FUTURE IMPLICATIONS: An umbilical laparoendoscopic single-site access for bilateral gonadectomy appears to be the first choice approach as leaves no visible incision and diminishes the psychological impact of surgery in a patient with CAIS absolutely reassured as female. KeyPort, a single port access with duo-rotate instruments developed by Richard Wolf facilitates this surgery and allows excellent cosmetic results.

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

Science.gov (United States)

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3-6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.

Androgens and Hypertension in Men and Women: a Unifying View.

Science.gov (United States)

Moretti, Costanzo; Lanzolla, Giulia; Moretti, Marta; Gnessi, Lucio; Carmina, Enrico

2017-05-01

This review was designed to revaluate the androgen role on the mechanisms of hypertension and cardiovascular risks in both men and women. Sex steroids are involved in the regulation of blood pressure, but pathophysiological mechanism is not well understood. Androgens have an important effect on metabolism, adipose and endothelial cell function, and cardiovascular risk in both men and women. A focal point in this contest is represented by the possible gender-specific regulation of different tissues and in particular of the adipose cell. Available data confirm that androgen deficiency is linked to increased prevalence of hypertension and cardiovascular diseases. Adipocyte dysfunction seems to be the main involved mechanism. Androgen replacement reduces inflammation state in man, protecting by metabolic syndrome progression. In women, androgen excess has been considered as promoting factor of cardiovascular risk. However, recent data suggest that excessive androgen production has little effect per se in inducing hypertension in young women of reproductive age. Also in postmenopausal women, data on relative androgen excess and hypertension are missing, while adrenal androgen deficiency has been associated to increased mortality. Molecular mechanisms linking androgen dysregulation to hypertension are almost Unknown, but they seem to be related to increased visceral fat, promoting a chronic inflammatory state through different mechanisms. One of these may involve the recruitment and over-activation of NF-kB, a ubiquitous transcription factor also expressed in adipose cells, where it may cause the production of cytokines and other immune factors. The NF-kB signalling pathway may also influence brown adipogenesis leading to the preferential enlargement of visceral adipocytes. Chronic inflammation and adipocyte dysfunction may alter endothelial function leading to hypertension. Both in men and in women, particularly in the post-menopausal period, hypoandrogenism seems to be

Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia

Directory of Open Access Journals (Sweden)

Sung Won Lee

2015-06-01

Full Text Available Gynecomastia is a benign enlargement of the male breast caused by the proliferation of glandular breast tissue. Determining the various causes of gynecomastia such as physiological causes, drugs, systemic diseases, and endocrine disorders is important. Androgen insensitivity syndrome (AIS is a rare endocrine disorder presenting with gynecomastia and is a disorder of male sexual differentiation caused by mutations within the androgen receptor gene. All individuals with AIS have the 46 XY karyotype, although AIS phenotypes can be classified as mild, partial or complete and can differ among both males and females including ambiguous genitalia or infertility in males. We experienced a case of partial AIS presenting with gynecomastia and identified the androgen receptor gene mutation.

Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth

International Nuclear Information System (INIS)

Liu, Shicheng; Yuan, Yiming; Okumura, Yutaka; Shinkai, Norihiro; Yamauchi, Hitoshi

2010-01-01

The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser 81 and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [ 3 H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.

Androgen receptor activation: a prospective therapeutic target for bladder cancer?

Science.gov (United States)

Mizushima, Taichi; Tirador, Kathleen A; Miyamoto, Hiroshi

2017-03-01

Patients with non-muscle-invasive or muscle-invasive bladder cancer undergoing surgery and currently available conventional therapy remain having a high risk of tumor recurrence or progression, respectively. Novel targeted molecular therapy is therefore expected to improve patient outcomes. Meanwhile, substantially higher incidence of bladder cancer in men has prompted research on androgen-mediated androgen receptor (AR) signaling in this malignancy. Indeed, preclinical evidence has suggested that AR signaling plays an important role in urothelial carcinogenesis and tumor outgrowth as well as resistance to some of the currently available conventional non-surgical therapies. Areas covered: We summarize and discuss available data suggesting the involvement of AR and its potential downstream targets in the development and progression of bladder cancer. Associations between AR signaling and sensitivity to cisplatin/doxorubicin or bacillus Calmette-Guérin treatment are also reviewed. Expert opinion: AR activation is likely to correlate with the promotion of urothelial carcinogenesis and cancer outgrowth as well as resistance to conventional therapies. Molecular therapy targeting the AR may thus provide effective chemopreventive and therapeutic approaches for urothelial cancer. Accordingly, bladder cancer can now be considered as an endocrine-related neoplasm. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to bladder cancer patients is anticipated.

Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

National Research Council Canada - National Science Library

Wang, Zhou

2004-01-01

.... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

National Research Council Canada - National Science Library

Wang, Zhou

2005-01-01

.... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

National Research Council Canada - National Science Library

Wang, Zhou

2003-01-01

.... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

Enzalutamide and blocking androgen receptor in advanced prostate cancer: lessons learnt from the history of drug development of antiandrogens.

Science.gov (United States)

Ito, Yusuke; Sadar, Marianne D

2018-01-01

Enzalutamide is a nonsteroidal antiandrogen for the treatment of metastatic castration-resistant prostate cancer (mCRPC) both before and after chemotherapy. Enzalutamide is more effective than its predecessor bicalutamide, which was analyzed in head-to-head studies of patients with CRPC. This family of nonsteroidal antiandrogens is now comprised of four drugs approved by the US Food and Drug Administration with two investigational drugs in clinical trials. Antiandrogens have been employed clinically for more than five decades to provide a rich resource of information. Steady-state concentration minimums (C min or trough) in the range of ~1-13 μg/mL are measured in patients at therapeutic doses. Interestingly, enzalutamide which is considered to have strong affinity for the androgen receptor (AR) requires C min levels >10 μg/mL. The sequence of antiandrogens and the clinical order of application in regard to other drugs that target the androgen axis remain of high interest. One novel first-in-class drug, called ralaniten, which binds to a unique region in the N-terminus domain of both the full-length and the truncated constitutively active splice variants of the AR, is currently in clinical trials for patients who previously received abiraterone, enzalutamide, or both. This highlights the trend to develop drugs with novel mechanisms of action and potentially differing mechanisms of resistance compared with antiandrogens. Better and more complete inhibition of the transcriptional activity of the AR appears to continue to provide improvements in the clinical management of mCRPC.

Characterization of niphatenones that inhibit androgen receptor N-terminal domain.

Directory of Open Access Journals (Sweden)

Carmen A Banuelos

Full Text Available Androgen ablation therapy causes a temporary reduction in tumor burden in patients with advanced prostate cancer. Unfortunately the malignancy will return to form lethal castration-recurrent prostate cancer (CRPC. The androgen receptor (AR remains transcriptionally active in CRPC in spite of castrate levels of androgens in the blood. AR transcriptional activity resides in its N-terminal domain (NTD. Possible mechanisms of continued AR transcriptional activity may include, at least in part, expression of constitutively active splice variants of AR that lack the C-terminal ligand-binding domain (LBD. Current therapies that target the AR LBD, would not be effective against these AR variants. Currently no drugs are clinically available that target the AR NTD which should be effective against these AR variants as well as full-length AR. Niphatenones were originally isolated and identified in active extracts from Niphates digitalis marine sponge. Here we begin to characterize the mechanism of niphatenones in blocking AR transcriptional activity. Both enantiomers had similar IC50 values of 6 µM for inhibiting the full-length AR in a functional transcriptional assay. However, (S-niphatenone had significantly better activity against the AR NTD compared to (R-niphatenone. Consistent with niphatenones binding to and inhibiting transactivation of AR NTD, niphatenones inhibited AR splice variant. Niphatenone did not affect the transcriptional activity of the related progesterone receptor, but slightly decreased glucocorticoid receptor (GR activity and covalently bound to GR activation function-1 (AF-1 region. Niphatenone blocked N/C interactions of AR without altering either AR protein levels or its intracellular localization in response to androgen. Alkylation with glutathione suggests that niphatenones are not a feasible scaffold for further drug development.

ENVIRONMENTAL ANDROGENS AND ANTIANDROGENS: AN EXPANDING CHEMICAL UNIVERSE

Science.gov (United States)

Within the last ten years, awareness has grown about environmental chemicals that display antiandrogenic or androgenic activity. While studies in the early 1990s focused on pesticides that acted as androgen receptor (AR) antagonists, it soon became evident that this was not the ...

Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

National Research Council Canada - National Science Library

Wang, Zhou

2006-01-01

.... Intermittent androgen ablation therapy (IAAT) may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes.

Science.gov (United States)

Xu, Ning; Chua, Angela K; Jiang, Hong; Liu, Ning-Ai; Goodarzi, Mark O

2014-08-01

Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study.

Palliative care for patients with cancer: do patients receive the care they consider important? A survey study.

Science.gov (United States)

Heins, Marianne; Hofstede, Jolien; Rijken, Mieke; Korevaar, Joke; Donker, Gé; Francke, Anneke

2018-04-17

In many countries, GPs and home care nurses are involved in care for patients with advanced cancer. Given the varied and complex needs of these patients, providing satisfactory care is a major challenge for them. We therefore aimed to study which aspects of care patients, GPs and home care nurses consider important and whether patients receive these aspects. Seventy-two Dutch patients with advanced cancer, 87 GPs and 26 home care nurses rated the importance of support when experiencing symptoms, respect for patients' autonomy and information provision. Patients also rated whether they received these aspects. Questionnaires were based on the CQ index palliative care. Almost all patients rated information provision and respect for their autonomy as important. The majority also rated support when suffering from specific symptoms as important, especially support when in pain. In general, patients received the care they considered important. However, 49% of those who considered it important to receive support when suffering from fatigue and 23% of those who wanted to receive information on the expected course of their illness did not receive this or only did so sometimes. For most patients with advanced cancer, the palliative care that they receive matches what they consider important. Support for patients experiencing fatigue may need more attention. When symptoms are difficult to control, GPs and nurses may still provide emotional support and practical advice. Furthermore, we recommend that GPs discuss patients' need for information about the expected course of their illness.

Estrogenic and anti-androgenic activities of 4-nitrophenol in diesel exhaust particles

International Nuclear Information System (INIS)

Li Chunmei; Taneda, Shinji; Suzuki, Akira K.; Furuta, Chie; Watanabe, Gen; Taya, Kazuyoshi

2006-01-01

A 4-nitrophenol (PNP) isolated from diesel exhaust particles (DEP) has been identified as a vasodilator. PNP is also a known degradation product of the insecticide parathion. We used uterotrophic and Hershberger assays to study the estrogenic and anti-androgenic activities of PNP in-vivo. In ovariectomized immature female rats injected subcutaneously with 1, 10, or 100 mg/kg PNP daily for 7 days, significant (P < 0.05) increases in uterine weight were seen in only those receiving 10 or 100 mg/kg PNP. Furthermore, in castrated immature male rats implanted with a silastic tube (length, 5 mm) containing crystalline testosterone and injected subcutaneously with 0.01, 0.1, or 1 mg/kg PNP daily for 5 days, those receiving the doses of 0.1 mg/kg showed significant (P < 0.05) weight decreases in seminal vesicles, ventral prostate, levator ani plus bulbocavernosus muscles, and glans penis. Plasma FSH and LH levels did not change in female rats but were significantly (P < 0.05) increased in male rats treated with 0.1 mg/kg PNP. These results clearly demonstrated that PNP has estrogenic and anti-androgenic activities in-vivo. Our results therefore suggest that diesel exhaust emissions and the degradation of parathion can lead to accumulation of PNP in air, water, and soil and thus could have serious deleterious effects on wildlife and human health

Estrogens and Androgens in Skeletal Physiology and Pathophysiology.

Science.gov (United States)

Almeida, Maria; Laurent, Michaël R; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A; Bouillon, Roger; Vanderschueren, Dirk; Manolagas, Stavros C

2017-01-01

Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. Copyright © 2017 the American Physiological Society.

Androgen receptors and serum testosterone levels identify different subsets of postmenopausal breast cancers

Directory of Open Access Journals (Sweden)

Secreto Giorgio

2012-12-01

Full Text Available Abstract Background Androgen receptors (AR are frequently expressed in breast cancers, but their implication in cancer growth is still controversial. In the present study, we further investigated the role of the androgen/AR pathway in breast cancer development. Methods AR expression was evaluated by immunochemistry in a cohort of 528 postmenopausal breast cancer patients previously examined for the association of serum testosterone levels with patient and tumor characteristics. AR expression was classified according to the percentage of stained cells: AR-absent (0% and AR-poorly (1%-30%, AR-moderately (>30%-60%, and AR-highly (>60% positive. Results Statistical analysis was performed in 451 patients who experienced natural menopause. AR-high expression was significantly related with low histologic grade and estrogen receptor (ER- and progesterone receptor (PR-positive status (P trendP=0.022, although a trend across the AR expression categories was not present. When women defined by ER status were analyzed separately, regression analysis in the ER-positive group showed a significant association of high testosterone levels with AR-highly-positive expression (OR 1.86; 95% CI, 1.10-3.16, but the association was essentially due to patients greater than or equal to 65 years (OR 2.42; 95% CI, 1.22-4.82. In ER-positive group, elevated testosterone levels appeared also associated with AR-absent expression, although the small number of patients in this category limited the appearance of significant effects (OR 1.92; 95% CI, 0.73–5.02: the association was present in both age groups ( Conclusions The findings in the present study confirm that testosterone levels are a marker of hormone-dependent breast cancer and suggest that the contemporary evaluation of ER status, AR expression, and circulating testosterone levels may identify different subsets of cancers whose growth may be influenced by androgens.

Androgenic anabolic steroids also impair right ventricular function.

Science.gov (United States)

Kasikcioglu, Erdem; Oflaz, Huseyin; Umman, Berrin; Bugra, Zehra

2009-05-01

Chronic anabolic steroid use suppresses left ventricular functions. However, there is no information regarding the chronic effects of anabolic steroids on right ventricular function which also plays a key role in global cardiac function. The main objective of the present study was to investigate the effects of androgenic anabolic steroids usage among athletes on remodeling the right part of the heart. Androgenic-anabolic steroids-using bodybuilders had smaller diastolic velocities of both ventricles than drug-free bodybuilders and sedentary counterparts. This study shows that androgenic anabolic steroids-using bodybuilders exhibited depressed diastolic functions of both ventricles.

Development of an androgen reporter gene assay (AR-LUX) utilizing a human cell line with an endogenously regulated androgen receptor

NARCIS (Netherlands)

Blankvoort, B.M.G.; Groene, E.M. de; Meeteren-Kreikamp, A.P. van; Witkamp, R.F.; Rodenburg, R.J.T.; Aarts, J.M.M.J.G.

2001-01-01

The aim of the work described in this report is to develop and characterize a cell-based androgen reporter assay. For this purpose, the androgen receptor (AR) expressing human breast cancer cell line T47D was stably transfected with a luciferase gene under transcriptional control of the PB-ARE-2

Anabolic-androgenic steroids for alcoholic liver disease

DEFF Research Database (Denmark)

Rambaldi, A; Gluud, C

2006-01-01

Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

Anabolic-androgenic steroids for alcoholic liver disease

DEFF Research Database (Denmark)

Rambaldi, A; Iaquinto, G; Gluud, C

2003-01-01

Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

Science.gov (United States)

2016-10-01

findings in the journal Cancer Research. 15. SUBJECT TERMS androgen receptor, prostate cancer, peptidomimetic conjugates, 16. SECURITY CLASSIFICATION OF...CAN-16-0385. Epub 2016 Aug 3, which is widely read by basic and clinical oncologists. The study was also highlighted in the journal Nature Reviews...This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received February 11

Environmental concentrations of an androgenic progestin disrupts the seasonal breeding cycle in male three-spined stickleback (Gasterosteus aculeatus).

Science.gov (United States)

Svensson, Johan; Fick, Jerker; Brandt, Ingvar; Brunström, Björn

2014-02-01

Synthetic steroid hormones from contraceptive pharmaceuticals have become global aquatic contaminants. Progestins, the synthetic analogs to progesterone, are receiving increasing attention as contaminants and have been shown to impair reproduction in fish and amphibians at low ng L(-1) concentrations. Certain progestins, such as levonorgestrel have androgenic properties and seem to be several orders of magnitude more potent in terms of reproductive impairment in fish than non-androgenic progestins and progestagens. We recently reported that levonorgestrel has strong androgenic effects in female three-spined sticklebacks (Gasterosteus aculeatus), including induction of the normally male-specific glue protein spiggin and suppression of vitellogenesis. In light of this we investigated if exposure to levonorgestrel could disrupt the highly androgen-dependent seasonal reproductive cycle in male sticklebacks. Male sticklebacks that were in the final stage of a breeding period were exposed to various concentrations of levonorgestrel for six weeks in winter conditions in terms of light and temperature, after which reproductive status was evaluated from gross morphology, histology and key gene transcript levels. During the experimental period the controls had transitioned from full breeding condition into the non-breeding state, including regression of secondary sex characteristics, cessation of spiggin production in the kidney, and resumption of spermatogenesis in the testes. This is ascribed to the natural drop in plasma androgen levels after breeding. However, in the groups concurrently exposed to levonorgestrel, transition to the non-breeding condition was dose-dependently inhibited. Our results show that levonorgestrel can disrupt the seasonal breeding cycle in male sticklebacks. The fitness costs of such an effect could be detrimental to natural stickleback populations. Some effects occurred at a levonorgestrel concentration of 6.5 ng L(-1), well within the range of

Microarray analysis of androgen-regulated gene expression in testis: the use of the androgen-binding protein (ABP-transgenic mouse as a model

Directory of Open Access Journals (Sweden)

Grossman Gail

2005-12-01

Full Text Available Abstract Background Spermatogenesis is an androgen-dependent process, yet the molecular mechanisms of androgens' actions in testis are poorly understood. Transgenic mice overexpressing rat androgen-binding protein (ABP in their testes have reduced levels of intratesticular androgens and, as a result, show a progressive impairment of spermatogenesis. We used this model to characterize changes in global gene expression in testis in response to reduced bioavailability of androgens. Methods Total RNA was extracted from testes of 30-day old transgenic and wild-type control mice, converted to cRNA, labeled with biotin, and hybridized to oligonucleotide microarrays. Microarray results were confirmed by real-time reverse transcription polymerase chain reaction. Results Three-hundred-eighty-one genes (3.05% of all transcripts represented on the chips were up-regulated and 198 genes (1.59% were down-regulated by at least a factor of 2 in the androgen-deficient animals compared to controls. Genes encoding membrane proteins, intracellular signaling molecules, enzymes, proteins participating in the immune response, and those involved in cytoskeleton organization were significantly overrepresented in the up-regulated group. Among the down-regulated transcripts, those coding for extracellular proteins were overrepresented most dramatically, followed by those related to proteolysis, cell adhesion, immune response, and growth factor, cytokine, and ion channel activities. Transcripts with the greatest potential impact on cellular activities included several transcription factors, intracellular signal transducers, secreted signaling molecules and enzymes, and various cell surface molecules. Major nodes in the up-regulated network were IL-6, AGT, MYC, and A2M, those in the down-regulated network were IL-2, -4, and -10, MAPK8, SOCS1, and CREB1. Conclusion Microarray analysis followed by gene ontology profiling and connectivity analysis identified several functional

Prolonged Hypogonadism in Males Following Withdrawal from Anabolic-Androgenic Steroids: an Underrecognized Problem

Science.gov (United States)

Kanayama, Gen; Hudson, James I.; DeLuca, James; Isaacs, Stephanie; Baggish, Aaron; Weiner, Rory; Bhasin, Shalender; Pope, Harrison G.

2015-01-01

Aims To assess the frequency and severity of hypogonadal symptoms in male long-term anabolic-androgenic steroid (AAS) misusers who have discontinued AAS use. Design Cross-sectional, naturalistic. Setting Outpatient facility. Participants Twenty-four male former long-term AAS users and 36 non-AAS-using weightlifters, recruited by advertisement in Massachusetts, USA. Five of the former users were currently receiving treatment with physiologic testosterone replacement, leaving 19 untreated users for the numerical comparisons below. Measurements The Structured Clinical Interview for DSM-IV, questions regarding history of AAS use, physical examination, serum hormone determinations, and the International Index of Erectile Function (IIEF). Findings Compared with the 36 non-AAS-using weightlifters, the 19 untreated former AAS users displayed significantly smaller testicular volumes (estimated difference [95% confidence interval (CI)]: 2.3 [0.1, 4.5] ml; p = 0.042) and lower serum testosterone levels (estimated difference: 131 [25, 227] dL; p = 0.009), with five users showing testosterone levels below 200 ng/dL despite abstinence from AAS for 3–26 months. Untreated former users also displayed significantly lower scores on the IIEF Sexual Desire subscale (estimated difference: 2.4 [1.3, 3.5] points on a 10-point scale; p treatment. Conclusions Among long-term anabolic-androgenic steroid misusers, anabolic-androgenic steroid-withdrawal hypogonadism appears to be common, frequently prolonged, and associated with substantial morbidity. PMID:25598171

Insulin hypersecretion together with high luteinizing hormone concentration augments androgen secretion in oral glucose tolerance test in women with polycystic ovarian disease.

Science.gov (United States)

Anttila, L; Koskinen, P; Jaatinen, T A; Erkkola, R; Irjala, K; Ruutiainen, K

1993-08-01

Female hyperandrogenism is often associated with hyperinsulinaemia and insulin resistance. We evaluated the hormone responses in an oral glucose tolerance test to investigate the interactions of gonadotrophins, insulin, C-peptide and androgens in women with polycystic ovarian disease (PCOD). In 28 patients with ultrasonographically diagnosed PCOD, hyperinsulinaemia and insulin resistance were mainly associated with obesity. Both basal and cumulative sum of insulin to C-peptide ratios were high in obese subjects, suggesting decreasing hepatic removal of insulin caused by obesity. Nevertheless, in some lean PCOD women, despite normal fasting insulin concentrations, insulin hypersecretion existed. The mean concentration of testosterone decreased significantly during the oral glucose tolerance test both in PCOD and control women, and of androstenedione in the PCOD patients only. However, an increase in androgen responses was found in a subgroup of PCOD patients, who had both elevated luteinizing hormone (LH) concentrations and hyperinsulinaemic response to oral glucose. In the remaining PCOD patients an inverse correlation between LH and insulin was found. The patients with hyperinsulinaemia together with LH hypersecretion may represent a subgroup of PCOD with deranged regulation of androgen secretion.

Post-operative neuromuscular function of patients receiving non ...

African Journals Online (AJOL)

Objectives: To determine the number of patients whose non-depolarising muscle relaxation is adequately reversed. To define factors that contribute to reversal. Design: A cross sectional study. Setting: Universitas Hospital recovery room over a 2 month period. Subjects: Patients that received non-depolarising muscle ...

Prostate cancer patient subsets showing improved bNED control with adjuvant androgen deprivation

International Nuclear Information System (INIS)

Anderson, Penny R.; Hanlon, Alexandra L.; Movsas, Benjamin; Hanks, Gerald E.

1997-01-01

Purpose: Cooperative groups have investigated the outcome of androgen deprivation therapy combined with radiation therapy in prostate cancer patients with variable pretreatment prognostic indicators. This report describes an objective means of selecting patients for adjuvant hormonal therapy by a retrospective matched case/control comparison of outcome between patients with specific pretreatment characteristics who receive adjuvant hormones (RT + H) vs. patients with identical pretreatment characteristics treated with radiation therapy alone (RT). In addition, this report shows the 5-year bNED control for patients selected by this method for RT + H vs. RT alone. Methods and Materials: From (10(88)) to (12(93)), 517 T1-T3 NXM0 patients with known pretreatment PSA level were treated at Fox Chase Cancer Center. Four hundred fifty-nine of those patients were treated with RT alone while 58 were treated with RT + H. The patients were categorized according to putative prognostic factors indicative of bNED control, which include the palpation stage, Gleason score, and pretreatment PSA. We compared actuarial bNED control rates according to treatment group within each of the prognostic groups. In addition, we devised a retrospective matched case/control selection of RT patients for comparison with the RT + H group. Five-year bNED control was compared for the two treatment groups, excluding the best prognosis group, using 56 RT + H patients and 56 matched (by stage, grade, and pretreatment PSA level) controls randomly selected from the RT alone group. bNED control for the entire group of 517 patients was then analyzed multivariately using step-wise Cox regression to determine independent predictors of outcome. Covariates considered for entry into the model included stage (T1/T2AB vs. T2C/T3), grade (2-6 vs. 7-10), pretreatment PSA (0-15 vs. > 15), treatment (RT vs. RT + H), and center of prostate dose. bNED failure is defined as PSA ≥1.5 ngm/ml and rising on two consecutive

Patient-reported distress and survival among patients receiving definitive radiation therapy

Directory of Open Access Journals (Sweden)

Yacob Habboush, MD

2017-04-01

Conclusions: PRD before or during RT is a prognostic factor associated with decreased survival. Distress screening guidelines and interventions should be implemented for patients receiving definitive RT.

Androgenic suppression combined with radiotherapy for the treatment of prostate adenocarcinoma: a systematic review

International Nuclear Information System (INIS)

Sasse, André D; Sasse, Elisa; Carvalho, Albertina M; Macedo, Ligia T

2012-01-01

Locally advanced prostate cancer is often associated with elevated recurrence rates. Despite the modest response observed, external-beam radiotherapy has been the preferred treatment for this condition. More recent evidence from randomised trials has demonstrated clinical benefit with the combined use of androgen suppression in such cases. The aim of this meta-analysis is to compare the combination of distinct hormone therapy modalities versus radiotherapy alone for overall survival, disease-free survival and toxicity. Databases (MEDLINE, EMBASE, LILACS, Cochrane databases and ClinicalTrials.gov) were scanned for randomised clinical trials involving radiotherapy with or without androgen suppression in local prostate cancer. The search strategy included articles published until October 2011. The studies were examined and the data of interest were plotted for meta-analysis. Survival outcomes were reported as a hazard ratio with corresponding 95% confidence intervals. Data from ten trials published from 1988 to 2011 were included, comprising 6555 patients. There was a statistically significant advantage to the use of androgen suppression, in terms of both overall survival and disease free survival, when compared to radiotherapy alone. The use of long-term goserelin (up to three years) was the strategy providing the higher magnitude of clinical benefit. In contrast to goserelin, there were no trials evaluating the use of other luteinizing hormone-releasing hormone (LHRH) analogues as monotherapy. Complete hormonal blockade was not shown to be superior to goserelin monotherapy. Based on the findings of this systematic review, the evidence supports the use of androgen suppression with goserelin monotherapy as the standard treatment for patients with prostate cancer treated with radiotherapy, which are at high risk of recurrence or metastases

Variation of luteinizing hormone and androgens in oligomenorrhoea and its implications for the study of polycystic ovary syndrome

NARCIS (Netherlands)

van Hooff, M. H.; van der Meer, M.; Lambalk, C. B.; Schoemaker, J.

1999-01-01

We measured luteinizing hormone (LH) and androgen concentrations in patients at different phases of the oligomenorrhoeic cycle and compared the results with those of patients with normogonadotrophic amenorrhoea. Several blood samples separated by >/=7 days were obtained from each of 72 patients with

Anti-androgen effects of cypermethrin on the amino- and carboxyl-terminal interaction of the androgen receptor

International Nuclear Information System (INIS)

Hu, Jin-xia; Li, Yan-fang; Pan, Chen; Zhang, Jin-peng; Wang, Hong-mei; Li, Jing; Xu, Li-chun

2012-01-01

Graphical abstract: Both the known AR antagonist nilutamide and the pyrethroid insecticide cypermethrin inhibited DHT-induced AR N/C interaction in the mammalian two-hybrid assay. However, cypermethrin was a weaker androgen antagonist than nilutamide. Highlights: ► We have developed the mammalian two-hybrid assay. ► The assay displayed appropriate response to DHT and nilutamide. ► The N/C interaction was induced by DHT in a dose-dependent manner. ► Nilutamide inhibited DHT-induced AR N/C interaction. ► Cypermethrin exhibits inhibitory effects on DHT-induced AR N/C interaction. -- Abstract: The pyrethroid insecticide, cypermethrin has been demonstrated to be an environmental anti-androgen in the androgen receptor (AR) reporter gene assay. The amino- and carboxyl-terminal (N/C) interaction is required for transcription potential of the AR. In order to characterize the anti-androgen effects of cypermethrin involved in the N/C interaction of AR, the mammalian two-hybrid assay has been developed in the study. The fusion vectors pVP16-ARNTD, pM-ARLBD and the pG5CAT Reporter Vector were cotransfected into the CV-1 cells. The assay displayed appropriate response to the potent, classical AR agonist 5α-dihydrotestosterone (DHT) and known AR antagonist nilutamide. The N/C interaction was induced by DHT from 10 −11 M to 10 −5 M in a dose-dependent manner. Nilutamide did not activate N/C interaction, while inhibited DHT-induced AR N/C interaction at the concentrations from 10 −7 M to 10 −5 M. Treatment of CV-1 cells with cypermethrin alone did not activate the reporter CAT. Cypermethrin significantly decreased the DHT-induced reporter CAT expression at the higher concentration of 10 −5 M. The mammalian two-hybrid assay provides a promising tool both for defining mechanism involved in AR N/C interaction of EDCs and for screening of chemicals with androgen agonistic and antagonistic activities. Cypermethrin exhibits inhibitory effects on the DHT-induced AR N

The effect of androgen deprivation on the early changes in prostate volume following transperineal ultrasound guided interstitial therapy for localized carcinoma of the prostate

Energy Technology Data Exchange (ETDEWEB)

Whittington, Richard; Broderick, Gregory A; Arger, Peter; Malkowicz, S Bruce; Epperson, Robert D; Arjomandy, Bijan; Kassaee, Alireza

1999-07-15

Purpose: To determine the change in volume of the prostate as a result of neoadjuvant androgen deprivation prior to prostate implant and in the early postimplant period following transperineal ultrasound guided palladium-103 brachytherapy for early-stage prostate cancer. Methods and Materials: Sixty-nine men received 3 to 6 months of androgen deprivation therapy followed by treatment planning ultrasound followed 4 to 8 weeks later by palladium-103 implant of the prostate. All patients had clinical and radiographic stage T1c-T2b adenocarcinoma of the prostate. A second ultrasound study was carried out 11 to 13 days following the implant to determine the change in volume of the prostate as a result of the implant. The prehormonal and preimplant volumes were compared to the postimplant volume to determine the effect of hormones and brachytherapy on prostate volume. Results: The median decrease in prostate volume as a result of androgen deprivation was 33% among the 54 patients with prostate volume determinations prior to hormonal therapy. The reduction in volume was greatest in the quartile of men with the largest initial gland volume (59%) and least in the quartile of men with smallest glands (10%). The median reduction in prostate volume between the treatment planning ultrasound and the follow-up study after implant was 3%, but 23 (33%) patients had an increase in prostate volume, including 16 (23%) who had an increase in volume >20%; 11 of these patients (16%) had an increase in volume >30%. The time course of development and resolution of this edema is not known. The severity of the edema was not related to initial or preimplant prostate volume or duration of hormonal therapy. Conclusions: Prostate edema may significantly affect the dose delivered to the prostate following transperineal ultrasound guided brachytherapy. The effect on the actual delivered dose will be greater when shorter lived isotopes are used. It remains to be observed whether this edema will

Gene Polymorphism-related Individual and Interracial Differences in the Outcomes of Androgen Deprivation Therapy for Prostate Cancer.

Science.gov (United States)

Fujimoto, Naohiro; Shiota, Masaki; Tomisaki, Ikko; Minato, Akinori

2017-06-01

Among patients with prostate cancer, the prognosis after androgen deprivation therapy differs significantly among individuals and among races; however, the reasons underlying these differences are poorly understood. Several single nucleotide polymorphisms in genes associated with prostate cancer progression or castration resistance might serve as the host factor that influences prognosis and, thus, accounts for these individual and racial gaps in treatment outcomes. Accordingly, single nucleotide polymorphisms associated with treatment outcomes could be used as predictive and/or prognostic biomarkers for patient stratification and to identify personalized treatment and follow-up protocols. The present review has summarized the genetic polymorphisms that have been reported to associate with androgen deprivation therapy outcomes among patients with prostate cancer and compared the allele frequencies among different ethnic groups. Copyright © 2017 Elsevier Inc. All rights reserved.

Relationship between serum response factor and androgen receptor in prostate cancer.

Science.gov (United States)

Prencipe, Maria; O'Neill, Amanda; O'Hurley, Gillian; Nguyen, Lan K; Fabre, Aurelie; Bjartell, Anders; Gallagher, William M; Morrissey, Colm; Kay, Elaine W; Watson, R William

2015-11-01

Serum response factor (SRF) is an important transcription factor in castrate-resistant prostate cancer (CRPC). Since CRPC is associated with androgen receptor (AR) hypersensitivity, we investigated the relationship between SRF and AR. Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry. To investigate AR involvement in SRF response to androgen, AR expression was down-regulated using siRNA. This resulted in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in AR-negative PC346 DCC cells, which was only restored following AR over-expression. Next, SRF expression was down-regulated by siRNA, resulting in AR increased transcriptional activity in castrate-resistant LNCaP Abl cells but not in the parental LNCaP. This negative feedback loop in the resistant cells was confirmed by immunohistochemistry which showed a negative correlation between AR and SRF expression in CRPC bone metastases and a positive correlation in androgen-naïve prostatectomies. Cell proliferation was next assessed following SRF inhibition, demonstrating that SRF inhibition is more effective than AR inhibition in castrate-resistant cells. Our data support SRF as a promising therapeutic target in combination with current treatments. © 2015 Wiley Periodicals, Inc.

Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer

DEFF Research Database (Denmark)

Axcrona, Karol; Aaltomaa, Sirpa; da Silva, Carlos Martins

2012-01-01

Study Type--Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Androgen deprivation therapy (ADT) is commonly used as a primary treatment for patients with prostate cancer (PCa) who are not eligible for radical treatment options. ADT is also used...... in patients with PCa as neo-adjuvant hormone therapy to reduce prostate volume and down-stage the disease before radiotherapy with curative intent. The present study showed that ADT with the gonadotropin hormone-releasing hormone (GhRH) antagonist degarelix is non-inferior to combined treatment with the LHRH...... agonist goserelin and bicalutamide in terms of reducing prostate volume during the treatment period of 3 months. Degarelix treatment evokes, however, significantly better relief of lower urinary tract symptoms in patients having moderate and severe voiding problems....

Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test.

Science.gov (United States)

Rosenfield, Robert L; Mortensen, Monica; Wroblewski, Kristen; Littlejohn, Elizabeth; Ehrmann, David A

2011-11-01

Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A). Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4-7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all. Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671-0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, PPCOS-A, but present in 30% of PCOS-T (P PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese. Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction.

Prevalence of major depressive disorder in patients receiving beta-blocker therapy versus other medications.

Science.gov (United States)

Carney, R M; Rich, M W; teVelde, A; Saini, J; Clark, K; Freedland, K E

1987-08-01

Depression is believed to be a common side effect in patients receiving beta-blocker therapy. However, diagnoses of depression defined by current diagnostic criteria may not be more common in patients receiving beta-blockers than in patients with the same medical disorder receiving other medications. Seventy-seven patients undergoing elective cardiac catheterization for evaluation of chest pain received a semi-structured diagnostic psychiatric interview. Twenty-one percent of the patients receiving beta-blockers and 33 percent of the patients receiving medications other than beta-blockers met the current American Psychiatric Association criteria for major depressive disorder (DSM-III) (p = NS). The mean heart rate and state anxiety scores for patients taking beta-blockers were significantly lower than those measured in patients taking medications other than beta-blockers. No other medical or demographic differences were observed between the two groups. Despite the methodologic limitations of the study, there does not appear to be a difference in the point prevalence of depression between patients receiving beta-blockers and those receiving other medications.

Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting.

Science.gov (United States)

Luo, Jun; Attard, Gerhardt; Balk, Steven P; Bevan, Charlotte; Burnstein, Kerry; Cato, Laura; Cherkasov, Artem; De Bono, Johann S; Dong, Yan; Gao, Allen C; Gleave, Martin; Heemers, Hannelore; Kanayama, Mayuko; Kittler, Ralf; Lang, Joshua M; Lee, Richard J; Logothetis, Christopher J; Matusik, Robert; Plymate, Stephen; Sawyers, Charles L; Selth, Luke A; Soule, Howard; Tilley, Wayne; Weigel, Nancy L; Zoubeidi, Amina; Dehm, Scott M; Raj, Ganesh V

2018-05-01

Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC). Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs. The meeting "Mission Androgen Receptor Variants" was the second of its kind sponsored by the Prostate Cancer Foundation (PCF). This invitation-only event was attended by international leaders in the field and representatives from sponsoring organizations (PCF and industry sponsors). Eighteen faculty members gave short presentations, which were followed by in-depth discussions. Discussions focused on three thematic topics: (1) potential of AR-Vs as biomarkers of therapeutic resistance; (2) role of AR-Vs as functionally active CRPC progression drivers; and (3) utility of AR-Vs as therapeutic targets in CRPC. The three meeting organizers synthesized this meeting report, which is intended to summarize major data discussed at the meeting and identify key questions as well as strategies for addressing these questions. There was a critical consensus that further study of the AR-Vs is an important research focus in CRPC. Contrasting views and emphasis, each supported by data, were presented at the meeting, discussed among the participants, and synthesized in this report. This article highlights the state of knowledge and outlines the most pressing questions that need to be addressed to advance the AR-V field. Although further investigation is needed to delineate the role of androgen receptor (AR) variants in metastatic castration-resistant prostate cancer, advances in measurement science have enabled development of blood-based tests for treatment selection. Detection of AR variants (eg, AR-V7) identified a patient population with poor outcomes to existing AR

A phase II trial of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for local failures or advanced prostate cancer.

Science.gov (United States)

Amato, Robert; Stepankiw, Mika; Gonzales, Patricia

2013-06-01

Long-term hormonal ablation in prostate cancer is associated with decreased overall health and quality of life. Few reports emphasized the role of chemotherapy in the management of early stage prostate cancer. This study analyzed the safety and efficacy of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for patients identified as local failures or not eligible for prostatectomy or radiation therapy due to advanced disease presentation. Enrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy. Chemotherapy consisted of ketoconazole and doxorubicin for weeks 1, 3, and 5 and estramustine and docetaxel and for weeks 2, 4 and 6. During weeks 7 and 8, no treatment was received. Forty-six patients were enrolled, and forty-five patients were evaluable. Median progression-free survival (PFS) was 23.4 months. Median overall survival (OS) was 53.7 months. Out of 45 patients with measurable disease, 22 patients had an objective response: 9 patients achieved a complete response; 2 patients achieved a partial response; 10 patients achieved stable disease. Frequent grade 3 adverse events included elevated ALT (17 %), hypokalemia (13 %), and hypophosphatemia (13 %). Grade 4 adverse events were rare and included low bicarbonate (2 %), hypokalemia (2 %), leukocytopenia (2 %), and neutropenia (2 %). The treatment demonstrated clinical benefit in all patient subsets with minimal reversible treatment-related adverse events. Subgroup analysis suggests that having prior local therapy resulted in greater PFS and OS.

Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer.

Science.gov (United States)

Dalton, James T; Taylor, Ryan P; Mohler, Michael L; Steiner, Mitchell S

2013-12-01

This review highlights selective androgen receptor modulators (SARMs) as emerging agents in late-stage clinical development for the prevention and treatment of muscle wasting associated with cancer. Muscle wasting, including a loss of skeletal muscle, is a cancer-related symptom that begins early in the progression of cancer and affects a patient's quality of life, ability to tolerate chemotherapy, and survival. SARMs increase muscle mass and improve physical function in healthy and diseased individuals, and potentially may provide a new therapy for muscle wasting and cancer cachexia. SARMs modulate the same anabolic pathways targeted with classical steroidal androgens, but within the dose range in which expected effects on muscle mass and function are seen androgenic side-effects on prostate, skin, and hair have not been observed. Unlike testosterone, SARMs are orally active, nonaromatizable, nonvirilizing, and tissue-selective anabolic agents. Recent clinical efficacy data for LGD-4033, MK-0773, MK-3984, and enobosarm (GTx-024, ostarine, and S-22) are reviewed. Enobosarm, a nonsteroidal SARM, is the most well characterized clinically, and has consistently demonstrated increases in lean body mass and better physical function across several populations along with a lower hazard ratio for survival in cancer patients. Completed in May 2013, results for the Phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer1 (POWER1) and POWER2 evaluating enobosarm for the prevention and treatment of muscle wasting in patients with nonsmall cell lung cancer will be available soon, and will potentially establish a SARM, enobosarm, as the first drug for the prevention and treatment of muscle wasting in cancer patients.

Cardiotoxic effects of cocaine and anabolic-androgenic steroids in the athlete.

Science.gov (United States)

Welder, A A; Melchert, R B

1993-04-01

Cocaine and anabolic-androgenic steroid abuse have become major drug problems in the United States. Cocaine has been designated as "the drug of greatest national health concern" while as many as 1 million Americans have used or are currently using anabolic-androgenic steroids to promote athletic performance and/or improve physical appearance. Unfavorable cardiovascular events have been linked to both cocaine and anabolic-androgenic steroid abuse in healthy, physically active individuals. Deaths of several United States athletes in 1986 focused attention on the life-threatening cardiovascular consequences of cocaine abuse. Reports of myocardial injury with anabolic-androgenic steroid abuse are anecdotal. Nevertheless, case reports have illustrated the alarming cardiotoxic potential of these steroids in athletes. Anabolic-androgenic steroids were correlated to myocardial infarction in weight lifters and cardiomyopathy in a former professional football player. From the total emergency room episodes where cocaine was mentioned in 1990, approximately 66% of these episodes occurred in young individuals 18-29 years of age. Over 500,000 of the individuals currently taking anabolic-androgenic steroids for nonmedical purposes are high-school children. Because cocaine and anabolic-androgenic steroids are used improperly, more focus needs to be paid to the toxic mechanisms of their adverse effects. Therefore, the purpose of this review is to discuss mechanisms whereby exercise and/or exercise training may alter the cardiovascular responses to these drugs. Furthermore, we would like to illustrate that contrary to the popular belief, acute and chronic abuse of cocaine and anabolic-androgenic steroids have a negative impact on exercise performance.

Androgen receptor function links human sexual dimorphism to DNA methylation.

Directory of Open Access Journals (Sweden)

Ole Ammerpohl

Full Text Available Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases.

ANDROGENS REGULATE T47D CELLS MOTILITY AND INVASION THROUGH ACTIN CYTOSKELETON REMODELLING

Directory of Open Access Journals (Sweden)

Maria Magdalena Montt-Guevara

2016-09-01

Full Text Available The relationship between androgens and breast cancer is controversial. Androgens have complex effects on breast cancer progression and metastasis. Moreover, androgens receptor (AR is expressed in approximately 70% to 90% of invasive breast carcinomas, which has prognostic relevance in basal-like cancers and in triple negative breast cancers. Recent studies have associated the actin-binding proteins of the Ezrin-Radixin-Moesin (ERM family with metastasis in endocrine-sensitive cancers. We studied on T47D breast cancer cells whether androgens with different characteristics, such as testosterone (T, dihydrotestosterone (DHT and dehydroepiandrosterone (DHEA may regulate breast cancer cell motility and invasion through the control of actin remodelling. We demonstrate that androgens promote migration and invasion in T47D via Moesin activation. We show that T and DHEA exert their actions via the AR and estrogen receptor (ER, while the non aromatizable androgen – DHT only recruits AR. We further report that androgen induced significant changes in actin organization with pseudopodia along with membrane ruffles formation, and this process is mediated by Moesin. Our work identifies novel mechanisms of action of androgens on breast cancer cells. Through the modulation of Moesin, androgens alter the architecture of cytoskeleton in T47D breast cancer cell and promote cell migration and invasion. These results could help to understand the biological actions of androgens on breast cancer, and eventually to develop new strategies for treatment of breast cancer.

Where Do Patients With Cancer in Iowa Receive Radiation Therapy?

Science.gov (United States)

Ward, Marcia M.; Ullrich, Fred; Matthews, Kevin; Rushton, Gerard; Tracy, Roger; Goldstein, Michael A.; Bajorin, Dean F.; Kosty, Michael P.; Bruinooge, Suanna S.; Hanley, Amy; Jacobson, Geraldine M.; Lynch, Charles F.

2014-01-01

Purpose: Multiple studies have shown survival benefits in patients with cancer treated with radiation therapy, but access to treatment facilities has been found to limit its use. This study was undertaken to examine access issues in Iowa and determine a methodology for conducting a similar national analysis. Patients and Methods: All Iowa residents who received radiation therapy regardless of where they were diagnosed or treated were identified through the Iowa Cancer Registry (ICR). Radiation oncologists were identified through the Iowa Physician Information System (IPIS). Radiation facilities were identified through IPIS and classified using the Commission on Cancer accreditation standard. Results: Between 2004 and 2010, 113,885 invasive cancers in 106,603 patients, 28.5% of whom received radiation treatment, were entered in ICR. Mean and median travel times were 25.8 and 20.1 minutes, respectively, to the nearest facility but 42.4 and 29.1 minutes, respectively, to the patient's chosen treatment facility. Multivariable analysis predicting travel time showed significant relationships for disease site, age, residence location, and facility category. Residents of small and isolated rural towns traveled nearly 3× longer than urban residents to receive radiation therapy, as did patients using certain categories of facilities. Conclusion: Half of Iowa patients could reach their nearest facility in 20 minutes, but instead, they traveled 30 minutes on average to receive treatment. The findings identified certain groups of patients with cancer who chose more distant facilities. However, other groups of patients with cancer, namely those residing in rural areas, had less choice, and some had to travel considerably farther to radiation facilities than urban patients. PMID:24443730

Expression profiles and functional associations of endogenous androgen receptor and caveolin-1 in prostate cancer cell lines.

Science.gov (United States)

Bennett, Nigel C; Hooper, John D; Johnson, David W; Gobe, Glenda C

2014-05-01

In prostate cancer (PCa) patients, the protein target for androgen deprivation and blockade therapies is androgen receptor (AR). AR interacts with many proteins that function to either co-activate or co-repress its activity. Caveolin-1 (Cav-1) is not found in normal prostatic epithelium, but is found in PCa, and may be an AR co-regulator protein. We investigated cell line-specific signatures and associations of endogenous AR and Cav-1 in six PCa cell lines of known androgen sensitivity: LNCaP (androgen sensitive); 22Rv1 (androgen responsive); PC3, DU145, and ALVA41 (androgen non-reliant); and RWPE1 (non-malignant). Protein and mRNA expression profiles were compared and electron microscopy used to identify cells with caveolar structures. For cell lines expressing both AR and Cav-1, knockdown techniques using small interfering RNA against AR or Cav-1 were used to test whether diminished expression of one affected the other. Co-sedimentation of AR and Cav-1 was used to test their association. A reporter assay for AR genomic activity was utilized following Cav-1 knockdown. AR-expressing LNCaP and 22Rv1 cells had low endogenous Cav-1 mRNA and protein. Cell lines that expressed little or no AR (DU145, PC3, ALVA41, and RWPE1) expressed high endogenous levels of Cav-1. AR knockdown in LNCaP cells had little effect on Cav-1, but Cav-1 knockdown inhibited AR expression and genomic activity. These data show endogenous AR and Cav-1 mRNA and protein expression is inversely related in PCa cells, with Cav-1 acting on the androgen/AR signaling axis possibly as an AR co-activator, demonstrated by diminished AR genomic activity following Cav-1 knockdown. © 2013 Wiley Periodicals, Inc.

Ovarian overproduction of androgens

Science.gov (United States)

... the body's testosterone. Tumors of the ovaries and polycystic ovary syndrome (PCOS) can both cause too much androgen production. ... come back after they have been removed. In polycystic ovary syndrome, the following measures can reduce symptoms caused by ...

Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment.

Science.gov (United States)

Bachmann, Gloria; Bancroft, John; Braunstein, Glenn; Burger, Henry; Davis, Susan; Dennerstein, Lorraine; Goldstein, Irwin; Guay, Andre; Leiblum, Sandra; Lobo, Rogerio; Notelovitz, Morris; Rosen, Raymond; Sarrel, Philip; Sherwin, Barbara; Simon, James; Simpson, Evan; Shifren, Jan; Spark, Richard; Traish, Abdul

2002-04-01

To evaluate the evidence for and against androgen insufficiency as a cause of sexual and other health-related problems in women and to make recommendations regarding definition, diagnosis, and assessment of androgen deficiency states in women. Evaluation of peer-review literature and consensus conference of international experts. Multinational conference in the United States. Premenopausal and postmenopausal women with androgen deficiency. Evaluation of peer-review literature and development of consensus panel guidelines. The term "female androgen insufficiency" was defined as consisting of a pattern of clinical symptoms in the presence of decreased bioavailable T and normal estrogen status. Currently available assays were found to be lacking in sensitivity and reliability at the lower ranges, and the need for an equilibrium dialysis measure was strongly emphasized. Causes of androgen insufficiency in women were classified as ovarian, adrenal, hypothalamic-pituitary, drug-related, and idiopathic. A simplified management algorithm and clinical guidelines were proposed to assist clinicians in diagnosis and assessment. Androgen replacement is currently available in several forms, although none has been approved for treatment of sexual dysfunction or other common symptoms of female androgen insufficiency. Potential risks associated with treatment were identified, and the need for informed consent and careful monitoring was noted. Finally, the panel identified key goals and priorities for future research. A new definition of androgen insufficiency in women has been proposed along with consensus-based guidelines for clinical assessment and diagnosis. A simplified management algorithm for women with low androgen in the presence of clinical symptoms and normal estrogen status has also been proposed.

Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells.

Science.gov (United States)

Olson, Brian M; Gamat, Melissa; Seliski, Joseph; Sawicki, Thomas; Jeffery, Justin; Ellis, Leigh; Drake, Charles G; Weichert, Jamey; McNeel, Douglas G

2017-12-01

Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anticancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR. Androgen deprivation increased AR expression in human and murine prostate tumor cells in vitro and in vivo The increased expression persisted over time. Increased AR expression was associated with recognition and cytolytic activity by AR-specific T cells. Furthermore, ADT combined with vaccination, specifically a DNA vaccine encoding the ligand-binding domain of the AR, led to improved antitumor responses as measured by tumor volumes and delays in the emergence of castrate-resistant prostate tumors in two murine prostate cancer models (Myc-CaP and prostate-specific PTEN-deficient mice). Together, these data suggest that ADT combined with AR-directed immunotherapy targets a major mechanism of resistance, overexpression of the AR. This combination may be more effective than ADT combined with other immunotherapeutic approaches. Cancer Immunol Res; 5(12); 1074-85. ©2017 AACR . ©2017 American Association for Cancer Research.

[Management of patients with bronchial asthma received general anesthesia and surgical intervention].

Science.gov (United States)

To, Masako; Tajima, Makoto; Ogawa, Cyuhei; Otomo, Mamoru; Suzuki, Naohito; Sano, Yasuyuki

2002-01-01

Stimulation to bronchial mucosa is one of the major risk factor of asthma attack. When patients receive surgical intervention and general anesthesia, they are always exposed to stimulation to bronchial mucosa. Prevention method of bronchial asthma attack during surgical intervention is not established yet. We investigated that clinical course of patients with bronchial asthma who received general anesthesia and surgical intervention. Seventy-six patients with bronchial asthma were received general anesthesia and surgical intervention from 1993 to 1998. Twenty-four patients were mild asthmatic patients, 39 were moderate asthmatic patients and 13 were severe asthmatic patients. Preoperative treatment for preventing asthma attack was as follows; Eight patients were given intravenous infusion of aminophylline before operation. Fifty-two patients were given intravenous infusion of aminophylline and hydrocortisone before operation. Three patients were given intravenous infusion of hydrocortisone for consecutive 3 days before operation. Thirteen patients were given no treatment for preventing asthma attack. One patient was suffered from asthma attack during operation. She was given no preventing treatment for asthma attack before operation. Three patients were suffered from asthma attack after operation. No wound dehiscence was observed in all patients. To prevent asthma attack during operation, intravenous infusion of steroid before operation is recommended, when patients with asthma receive general anesthesia and surgical intervention.

Female adipocyte androgen synthesis and the effects of insulin

Directory of Open Access Journals (Sweden)

David Cadagan

2014-01-01

Full Text Available The metabolic syndrome is a cluster of metabolic disorders characterized by insulin resistance and hyperinsulinaemia, and its presence can increase the risk of cardiovascular disease significantly. The metabolic syndrome is associated with increased circulating androgen levels in women, which may originate from the ovaries and adrenal glands. Adipocytes are also able to synthesise steroid hormones, and this output has been hypothesised to increase with elevated insulin plasma concentrations. However, the contribution of the adipocytes to the circulating androgen levels in women with metabolic syndrome is limited and the effects of insulin are not fully understood. The aim of this study was to investigate the presence of steroid precursors and synthetic enzymes in human adipocyte biopsies as markers of possible adipocyte androgen synthesis. We examined pre and mature adipocytes taken from tissue biopsies of abdominal subcutaneous adipose tissue of participating women from the Department of Obstetrics and Gynaecology, of the Royal Derby Hospital. The results showed the potential for localised adipocyte androgen synthesis through the presence of the androgen precursor progesterone, as well as the steroid-converting enzyme 17α-hydroxylase. Furthermore, we found the controlled secretion of androstenedione in vitro and that insulin treatment caused levels to increase. Continued examination of a localised source of androgen production is therefore of clinical relevance due to its influence on adipocyte metabolism, its negative impact on female steroidogenic homeostasis, and the possible aggravation this may have when associated to obesity and obesity related metabolic abnormalities such as hyperinsulinaemia.

Plasma Aluminum Concentrations in Pediatric Patients Receiving Long-Term Parenteral Nutrition.

Science.gov (United States)

Courtney-Martin, Glenda; Kosar, Christina; Campbell, Alison; Avitzur, Yaron; Wales, Paul W; Steinberg, Karen; Harrison, Debra; Chambers, Kathryn

2015-07-01

Patients receiving long-term parenteral nutrition (PN) are at increased risk of aluminium (Al) toxicity because of bypass of the gastrointestinal tract during PN infusion. Complications of Al toxicity include metabolic bone disease (MBD), Al-associated encephalopathy in adults, and impaired neurological development in preterm infants. Unlike the United States, there are no regulations regarding Al content of large- and small-volume parenterals in Canada. We, therefore, aimed to present our data on plasma Al concentration and Al intake from our cohort of pediatric patients receiving long-term PN. Plasma Al concentration was retrospectively gathered from the patient charts of all 27 patients with intestinal failure (IF) receiving long-term PN at The Hospital for Sick Children, Toronto, Canada, and compared with age- and sex-matched controls recruited for comparison. In addition, Al concentration was measured in PN samples collected from 10 randomly selected patients with IF and used to determine their Al intake. The plasma Al concentration of patients with IF receiving long-term PN was significantly higher than that of control participants (1195 ± 710 vs 142 ± 63 nmol/L; P Parenteral and Enteral Nutrition.

Partial androgen deficiency, depression and testosterone treatment in aging men.

Science.gov (United States)

Amore, Mario; Scarlatti, Fabiano; Quarta, Antonio Lucio; Tagariello, Pietro

2009-02-01

This study provides a critical review of the literature on depressive symptoms of partial androgen deficiency (PADAM) and their treatment with Testosterone (T). PADAM in aging males is responsible for a variety of behavioral symptoms, such as weakness, decreased libido and erectile dysfunction, lower psychological vitality, depressive mood, anxiety, insomnia, difficulty in concentrating, and memory impairment. The psychological and behavioural aspects of PADAM may overlap with signs and symptoms of major depression. Evidence of the relationship between androgen deficiency and male depression comes from studies that have assessed depression in hypogonadal subjects, the association between low T level and male depressive illness, and the antidepressant action of androgen replacement. The etiology of depressive symptoms of PADAM is multifactorial, and results from the interaction of the biological and psychosocial changes that take place during the mid-life transition. Although data derived from androgen treatment trials and androgen replacement do not support T treatment or replacement as more efficacious than placebo for major depressive disorder (MDD), the clinical impression is that, in some sub-threshold depressive syndromes, T may lead to antidepressant benefits.

Blood androgen levels in male baboons throughout the year

International Nuclear Information System (INIS)

Taranov, A.G.; Goncharov, N.P.

1986-01-01

This paper describes a study of possible dependence of the androgen level in male baboons on the time of year. Plasma was obtained by centrifugation of the blood at 3000 rpm and the following androgens were determined by radioimmunoassay, using chromatographic separation of the steroids on columns with celite: testosterone, 5s-dihydrotestosterone, and dehydroepiandrosterone. Plasma steriod concentrations were calculated and the results were subjected to statistical analysis by Students test. Seasonal change in the concentration of steroids in the animals' blood plasma were discovered. The results of androgen assay throughout the year and determination of their mean annual concentrations are shown

Alteration in follistatin gene expression detected in prenatally androgenized rats.

Science.gov (United States)

Salehi Jahromi, Marziyeh; Ramezani Tehrani, Fahimeh; Hill, Jennifer W; Noroozzadeh, Mahsa; Zarkesh, Maryam; Ghasemi, Asghar; Zadeh-Vakili, Azita

2017-06-01

Impaired ovarian follicle development, the hallmark of polycystic ovarian syndrome (PCOS), is believed to be due to the changes in expression of related genes such as follistatin (FST). Expression of FST gene and methylation level of its promoter in theca cells from adult female rats, prenatally exposed to androgen excess, during different phases of the estrus cycle was determined and compared with controls. Eight pregnant Wistar rats (experimental group) were treated by subcutaneous injection of 5 mg free testosterone on day 20 of pregnancy, while controls (n = 8) received 500 ml solvent. Based on observed vaginal smear, adult female offspring of mothers were divided into three groups. Levels of serum steroidogenic sexual hormones and gonadotropins, expression and promoter methylation of the FST gene were measured using ELISA, cyber-green real-time PCR and bisulfite sequence PCR (BSP), respectively. Compared to controls, the relative expression of FST gene in the treated group decreased overall by 0.85 fold; despite significant changes in different phases, but no significant differences in methylation of FST promoter. Our results reveal that manifestation of PCOS-like phenotype following prenatal exposure to excess androgen is associated with irregularity in expression of the FST gene during the estrus cycle.

Impact of androgen and dietary advanced glycation end products on female rat liver.

Science.gov (United States)

Palioura, Eleni; Palimeri, Sotiria; Piperi, Christina; Sakellariou, Stratigoula; Kandaraki, Eleni; Sergentanis, Theodoros; Levidou, Georgia; Agrogiannis, George; Papalois, Apostolos; Korkolopoulou, Penelope; Diamanti-Kandarakis, Evanthia; Papavassiliou, Athanasios G

2015-01-01

Advanced glycation end products (AGEs) have been related to a wide range of liver disorders including hyperandrogenic states such as the Polycystic Ovary Syndrome (PCOS). The aim of the present study is to evaluate the potential impact of dietary glycotoxins exposure and androgen excess on hepatic histology and biochemistry in an androgenized female rat model. The study population consisted of 80 female Wistar rats, divided in 3 groups, a group of prepubertal (Group A, n=30) and adult rats (Group B, n=20) that were androgenized via subcutaneous implantation of dihydrotestosterone-containing pellets as well as a group of adult non-androgenized rodents (Group C, n=30). All groups were randomly assigned either to a high-AGE or low-AGE diet for 3 months. Rats fed with a high-AGE diet exhibited significantly elevated levels of gamma-glutamyl transferase (x03B3;GT) (p≤0.0002) and indices of AGE immunostaining in liver tissue (pandrogenized animals (p=0.0002). Androgenization per se constitutes an aggravating factor as demonstrated by the elevated x03B3;GT levels in adult androgenized animals compared to non-androgenized, independent of diet content (p=0.0002) and by the elevated AST and alanine aminotransferase (ALT) levels in low-AGE subgroups (adult androgenized vs. non-androgenized, p=0.0002) followed by increased immunohistochemical AGE deposition in hepatocytes of the latter categories (p=0.0007). The present study suggests that androgens and glycotoxins may contribute synergistically to distort hepatic physiology and function as observed in hyperandrogenic conditions. © 2015 The Author(s) Published by S. Karger AG, Basel.

Intermittent Versus Continuous Androgen Deprivation Therapy for Prostate Cancer: A Systematic Review and Meta-analysis

Directory of Open Access Journals (Sweden)

Yu-xiao ZHENG

2018-03-01

Full Text Available Objective: The strategy of androgen deprivation therapy (ADT applied in patients with prostate cancer (PCa to achieve optimal clinical and oncologic outcomes has been a longstanding debate. The objective of our study was to perform a metaanalysis to compare the efficacy, quality of life and adverse events profile of intermittent versus continuous androgen deprivation for prostate cancer. Methods: We searched PubMed, EMBASE and Web of Science to extract the basic characteristics. Besides, data of endpoint such as overall survival (OS, progression free survival (PFS, cancer-specific survival (CSS and time to progression (TTP as well as quality of life (QoL were also collected. In addition, the results were expressed as hazard ratio (HR with 95% confidence interval (CI. Results: 17 articles including a total 6,733 patients with any stage of PCa were included in our review. No significant differences were found in PFS (HR = 0.93, 95% CI: 0.83-1.03, TTP (HR = 0.96, 95% CI: 0.84-1.07 between intermittent androgen deprivation (IAD and continuous androgen deprivation (CAD, whereas CAD showed benefits associated with OS (HR = 0.92, 95% CI: 0.85-0.98 and CSS (HR = 0.86, 95% CI: 0.74-0.98. In addition, IAD might have a superior outcome compared with CAD, especially in sexual functioning and headache favoring. Controversial outcomes were also seen in some aspects such as hot flushes, gynecomastia, breast pain or fatigue. Conclusion: PFS and TTP were similar between IAD and CAD, whereas CAD showed benefits associated with OS and CSS. IAD might have benefits in QoL and have less adverse effects, especially in sexual dysfunction and headache.

Iodine Supplementation for Pediatric Patients Receiving Long-Term Parenteral Nutrition.

Science.gov (United States)

Santoro, Jonathan D; Nespor, Colleen; Poole, Robert L; Kerner, John A

2016-04-01

Patients dependent on parenteral nutrition (PN) are among a group at risk of developing iodine deficiency. Supplementation with iodine in this population has been debated in a number of studies, resulting in variable clinical practices. The Committee on Clinical Practice Issues of the American Society for Clinical Nutrition recommends a dose of 1 mcg/kg/d of parenteral iodine for patients receiving PN. At our institution, PN trace elements do not include iodine, although this is not the case internationally. Our study sought to assess iodine levels and thyroid function in a cohort of PN-dependent pediatric patients. A retrospective analysis studied 32 pediatric patients with a variety of medical diagnoses who received PN as a primary means of nutrition for 6 months or longer. Patients received variable proportions of their total caloric intake as PN, which ranged from 14%-100%. Iodine and thyroid function levels were obtained by serum sampling. No patient in our cohort of 32 demonstrated thyroid dysfunction or developed iodine deficiency. The length of time on PN and the percentage of total nutrition intake as PN were not associated with iodine levels (P Parenteral and Enteral Nutrition.

Vitamin D is associated with bioavailability of androgens in eumenorrheic women with prior pregnancy loss.

Science.gov (United States)

Kuhr, Daniel L; Sjaarda, Lindsey A; Alkhalaf, Zeina; Omosigho, Ukpebo R; Connell, Matthew T; Silver, Robert M; Kim, Keewan; Perkins, Neil J; Holland, Tiffany L; Plowden, Torie C; Schisterman, Enrique F; Mumford, Sunni L

2018-06-01

Prior studies have reported mixed results regarding relationships between vitamin D, androgens, and sex hormone-binding globulin in patients with polycystic ovary syndrome. However, less is known regarding these associations in eumenorrheic, premenopausal women. Our objective was to study the relationships between serum vitamin D and androgen biomarkers in eumenorrheic women with a history of pregnancy loss who were attempting pregnancy. This was an analysis of a cohort of 1191 participants from the Effects of Aspirin in Gestation and Reproduction trial (2006-2012). Participants were attempting to conceive, aged 18-40 years, with 1-2 documented prior pregnancy losses and no history of infertility, and recruited from 4 academic medical centers in the United States. Serum vitamin D (25-hydroxyvitamin D) and hormone concentrations were measured at baseline. Vitamin D concentration was negatively associated with free androgen index (percentage change [95% confidence interval, -5% (-8% to -2%)] per 10 ng/mL increase) and positively associated with sex hormone-binding globulin (95% confidence interval, 4% [2-7%]), although not with total testosterone, free testosterone, or dehydroepiandrosterone sulfate after adjusting for age, body mass index, smoking status, race, income, education, physical activity, and season of blood draw. Overall, vitamin D was associated with sex hormone-binding globulin and free androgen index in eumenorrheic women with prior pregnancy loss, suggesting that vitamin D may play a role in the bioavailability of androgens in eumenorrheic women. We are limited in making assessments regarding directionality, given the cross-sectional nature of our study. Copyright © 2018. Published by Elsevier Inc.

Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring.

Science.gov (United States)

Abbott, David H; Bruns, Cristin R; Barnett, Deborah K; Dunaif, Andrea; Goodfriend, Theodore L; Dumesic, Daniel A; Tarantal, Alice F

2010-11-01

Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155-175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data.

Science.gov (United States)

Bozovic-Spasojevic, Ivana; Zardavas, Dimitrios; Brohée, Sylvain; Ameye, Lieveke; Fumagalli, Debora; Ades, Felipe; de Azambuja, Evandro; Bareche, Yacine; Piccart, Martine; Paesmans, Marianne; Sotiriou, Christos

2017-06-01

Purpose: Androgen receptor (AR) expression has been observed in about 70% of patients with breast cancer, but its prognostic role remains uncertain. Experimental Design: To assess the prognostic role of AR expression in early-stage breast cancer, we performed a meta-analysis of studies that evaluated the impact of AR at the protein and gene expression level on disease-free survival (DFS) and/or overall survival (OS). Eligible studies were identified by systematic review of electronic databases using the MeSH-terms "breast neoplasm" and "androgen receptor" and were selected after a qualitative assessment based on the REMARK criteria. A pooled gene expression analysis of 35 publicly available microarray data sets was also performed from patients with early-stage breast cancer with available gene expression and clinical outcome data. Results: Twenty-two of 33 eligible studies for the clinical meta-analysis, including 10,004 patients, were considered as evaluable for the current study after the qualitative assessment. AR positivity defined by IHC was associated with improved DFS in all patients with breast cancer [multivariate (M) analysis, HR 0.46; 95% confidence interval (CI) 0.37-0.58, P expression analysis. High AR mRNA levels were found to confer positive prognosis overall in terms of DFS (HR 0.82; 95% CI 0.72-0.92; P = 0.0007) and OS (HR 0.84; 95% CI, 0.75-0.94; P = 0.02) only in univariate analysis. Conclusions: Our analysis, conducted among more than 17,000 women with early-stage breast cancer included in clinical and gene expression analysis, demonstrates that AR positivity is associated with favorable clinical outcome. Clin Cancer Res; 23(11); 2702-12. ©2016 AACR . ©2016 American Association for Cancer Research.

The Views Of Cancer Patients On Receiving Bad News

Directory of Open Access Journals (Sweden)

Hatice Bostanoglu Fesci

2011-06-01

Full Text Available AIM: This study was performed in a descriptive matter to determine the views of inpatients at an oncology state hospital on receiving bad news. METHOD: The study sample consisted of 237 inpatients (155 females, 82 males at an oncology state hospital between October and November 2008 who were determined using the random sampling method and accepted participating in the study. The data collection tool used was a survey form that consisted of 24 questions related to the sociodemographic features and views on receiving bad news. RESULTS: The mean age of the study subjects was 53.1±13.9 (min.=18, max.=83. The patients were undergoing the treatment process in 84% and the diagnostic process in 16%. The bad news had been given by the physician in 87.8% and while in the physician's room in 74.8%. The patients had been told while receiving the bad news that 'there is a mass/problem/lesion/tumor and you will undergo surgery' in 47.7% while 24.9% had been told that they had cancer directly. The patients stated that they froze, fainted, were shocked, felt their life was shattered and experienced emotions such as sadness, fear, hopelessness, sorrow, disappointment, desperation, etc. at a rate of 93.7%. We found that 58.2% of the patients had not been given an opportunity to express their emotions when they received the bad news, 67.4% preferred to have a relative with them at the time, 40.9% felt that the bad news should be given in a special environment, 30% wanted the bad news to be given as soon as the diagnosis was known while 36.7% preferred being told everything about the disease when receiving the bad news CONCLUSION: Taking into account the information content, family participation, and the individual preferences of the patients regarding time and place when giving bad news and encouraging them to ask questions and express themselves may make it easier for the patients to cope with bad news. [TAF Prev Med Bull 2011; 10(3.000: 319-326

Ekspresi Gen CYP19 Aromatase, Estrogen, Androgen pada penderita Periodontitis Agresif

Directory of Open Access Journals (Sweden)

Dahlia Herawati

2016-11-01

Full Text Available Kepadatan tulang tubuh ditentukan oleh gen CYP19 aromatase, hormon estrogen dan androgen. Pada periodontitis agresif terjadi perkembangan cepat kerusakan tulang alveolar, dan kerusakan tulang alveoler tersebut tidak diimbangioleh regenerasi tulang. Tujuan penelitian ini adalah menunjukkan ekspresi gen CYP19 aromatase, estrogen, androgen pada penderita periodontitis agresif agar dapat untuk menjadi pertimbangan pada saat melakukan perawatan periodontal. Metode penelitian, pemeriksaan ekspresi gen aromatse CYP19 berasal dari spesimen tulang alveolar menggunakan imunohistokimia, pengukuran hormon estrogen dan androgen dari serum menggunakan Vidas: Elfa. Hasil penelitian ekspresi gene CYP19 aromatase pada periodontitis agresif menunjukkan gambaran lebih rendah densitasnya dibandingkan pada nonperiodontitis. Estrogen dan androgen pad aperiodontitis agresif ada kecenderungan lebih rendah dibandingkan pada nonperiodontitis. Kesimpulan regenerasi tulang alveoler pad a periodontitis agresif terhambat karena sedikitnya gen CYP19 aromatase dan hormon estrogen dan androgen yang berperan pada pembentukan tulang alveoler kurang memadai.

Exercise Improves V˙O2max and Body Composition in Androgen Deprivation Therapy-treated Prostate Cancer Patients.

Science.gov (United States)

Wall, Bradley A; GALVãO, Daniel A; Fatehee, Naeem; Taaffe, Dennis R; Spry, Nigel; Joseph, David; Hebert, Jeffrey J; Newton, Robert U

2017-08-01

Prostate cancer is the most common cancer in men, and patients treated with androgen deprivation therapy (ADT) experience unfavorable changes in body composition and associated metabolic complications, which can increase the risk of cardiovascular disease. We examined the effect of a 6-month program of aerobic and resistance exercise aimed at improving body composition and cardiorespiratory health in this population. Ninety-seven men (43-90 yr) with localized prostate cancer receiving ADT were randomized to either exercise (EX, n = 50) or usual care (CON, n = 47). Supervised exercise was undertaken twice weekly at moderate to high intensity. Measures of cardiorespiratory capacity (V˙O2max), resting metabolic rate, central blood pressure, hemodynamic variables, blood markers, and body composition were assessed. There was a significant group-time interaction present for V˙O2max (P = 0.033) with a treatment effect for EX of 0.11 L·min (95% confidence interval [CI] = 0.04-0.19) (relative to body mass = 1.3 mL·kg·min, 95% CI = 0.3-2.3) and fat oxidation (P = 0.037) of 12.0 mg·min (95% CI = 2.3-21.7). Similarly, there was a significant improvement in glucose (P Body composition was enhanced for EX with adjusted mean differences in lean mass (P = 0.015) of 0.8 kg (95% CI = 0.3-1.3), total fat mass (P = 0.020) of -1.1 kg (95% CI = -1.8 to -0.5), and trunk fat mass (P body composition despite the adverse effects of hormone suppression. Combined aerobic and resistance training should be considered a key adjuvant component in men undergoing ADT for the treatment of prostate cancer.

A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids.

Science.gov (United States)

Pretorius, Elzette; Arlt, Wiebke; Storbeck, Karl-Heinz

2017-02-05

The abundant adrenal C19 steroid 11β-hydroxyandrostenedione (11OHA4) has been written off as a dead-end product of adrenal steroidogenesis. However, recent evidence has demonstrated that 11OHA4 is the precursor to the potent androgenic 11-oxygenated steroids, 11-ketotestosterone and 11-ketodihydrotestosterone, that bind and activate the human androgen receptor similarly to testosterone and DHT. The significance of this discovery becomes apparent when considering androgen dependent diseases such as castration resistant prostate cancer and diseases associated with androgen excess, e.g. congenital adrenal hyperplasia and polycystic ovary syndrome. In this review we describe the production and metabolism of 11-oxygenated steroids. We subsequently discuss their androgenic activity and highlight the putative role of these androgens in disease states. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Lack of benefit for the addition of androgen deprivation therapy to dose-escalated radiotherapy in the treatment of intermediate- and high-risk prostate cancer.

LENUS (Irish Health Repository)

Krauss, Daniel

2012-02-01

PURPOSE: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). METHODS AND MATERIALS: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng\\/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA >\\/=20, or Stage T3. Patients were additionally divided specifically by Gleason score, presence of palpable disease, and PSA level to further define subgroups benefitting from ADT. RESULTS: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason >\\/=8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. CONCLUSION: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.

Factors predicting hyperkalemia in patients with cirrhosis receiving spironolactone

International Nuclear Information System (INIS)

Abbas, Z.; Mumtaz, K.; Salam, A.; Jafri, W.

2003-01-01

Objective: To evaluate the factors leading to hyperkalemia in patients with cirrhosis receiving spironolactone. Results: Patients with hyperkalemia (K>5 mmol/l) had higher blood urea nitrogen, serum creatinine and bilirubin levels (p=0.004, 0.001 and 0.044 respectively). Their serum sodium and albumin levels were lower (p=0.000 and 0.017 respectively). They had advanced cirrhosis with high Pugh score (p=0.003). These patients were on higher dose of spironolactone (p=0.001). Multivariate analysis showed that dose of spironolactone > 100 mg/day, serum creatinine >1.3 mg/dl, persistence of ascites and edema, and female gender were important predictors of development of hyperkalemia. Conclusion: Patients with cirrhosis receiving high dose of the diuretic, having edema, ascites and high serum creatinine are at the greater risk of developing hyperkalemia during spironolactone therapy. (author)

ARA24/Ran enhances the androgen-dependent NH2- and COOH-terminal interaction of the androgen receptor

International Nuclear Information System (INIS)

Harada, Naoki; Ohmori, Yuji; Yamaji, Ryoichi; Higashimura, Yasuki; Okamoto, Kazuki; Isohashi, Fumihide; Nakano, Yoshihisa; Inui, Hiroshi

2008-01-01

The androgen receptor (AR) acts as an androgen-dependent transcription factor controlling the development of prostate tissue. Upon binding to androgen, AR undergoes a dynamic structural change leading to interaction between the NH 2 - and COOH-terminal regions of AR (N-C interaction). ARA24/Ran, which is a small GTPase, functions as an AR coactivator. Here, we report that ARA24/Ran enhances the N-C interaction of AR. The constitutively GTP- or GDP-bound form of ARA24/Ran repressed the AR N-C interaction. ARA24/Ran did not enhance the transcriptional activities of AR mutants that disrupt the N-C interaction. ARA24/Ran formed an endogenous protein complex with nuclear AR, but not cytoplasmic AR. Unlike SRC-1 with the positive activity for AR N-C interaction, ARA24/Ran did not enhance the transcriptional activity of the COOH-terminal domain-deleted AR mutant that is constitutively localized in the nucleus. These data demonstrate that ARA24/Ran increases AR transactivation by enhancing the AR N-C interaction in the nucleus

An Evaluation of Hepatotoxicity in Breast Cancer Patients Receiving ...

African Journals Online (AJOL)

hanumantp

investigation was a prospective study that was conducted in cancer patients receiving Inj. Doxorubicin .... patients. Pre-Chem o. I - Cycle. II - Cycle III - Cycle. IV - Cycle. 0. 1. 2. 3. 4 .... vitamin E, vitamin C, vitamin A, antioxidant components.

Assessing Selenium, Manganese, and Iodine Status in Pediatric Patients Receiving Parenteral Nutrition.

Science.gov (United States)

Johnsen, Jacob Clarke; Reese, Susan Anne; Mackay, Mark; Anderson, Collin R; Jackson, Daniel; Paul, Irasema Libertad

2017-08-01

Pediatric patients who are receiving parenteral nutrition (PN) unsupplemented with trace minerals can become deficient. Due to shortages in trace mineral products and the 2004 American Society for Parenteral and Enteral Nutrition report stating that individualized trace element supplementation may be warranted, a review was conducted concerning the trace minerals selenium (Se), manganese (Mn), and iodine (I). A retrospective review of pediatric patients receiving PN that contained Se and Mn was conducted to determine if a difference existed between them and patients receiving PN without Se and Mn. Statistical analysis was done to assess a difference between trace mineral levels and the time to deficiency between supplemented and unsupplemented patients. Unsupplemented I patients had urine I levels assessed to determine deficiencies in patients receiving PN. Plasma Se levels were measured at a mean of 20 days for supplemented patients (n = 131) and 19 days for nonsupplemented patients (n = 57) with no difference between groups ( P = .2973). Plasma Mn levels were measured at a mean of 28 days, showing no statistical difference ( P = .721). Of the 177 nonsupplemented I patients, 74% demonstrated I deficiencies without supplementation. Time to the development of a Se, Mn, or I deficiency is important to guide supplementation of exclusive PN in children when trace mineral products are short in supply. Our retrospective experience supports assessment of the trace minerals Se at 21 days and Mn at 30 days. It also suggests that some pediatric patients receiving PN are deficient in I.

Diagnostics and correction of metabolic disorders in patients with recurrent urolithiasis after endoscopic removal of stones

Directory of Open Access Journals (Sweden)

T. Kh. Nazarov

2015-01-01

Full Text Available The article is devoted to the problem of kidney stones. The authors provide the results of a study of 107 men aged 48 to 76 years, were divided into three groups – primary and two control groups. The main and the first control group consisted of 40 patients with recurrent urolithiasis without urinary tract obstruction after endoscopic stone removal and partial androgen deficiency. The second control group consisted of 27 healthy men aged 48 to 70 years. Patients for one year he was promoted endoscopic removal of urinary stones: transurethral nephrolithotripsy – 55 patients, and percutaneous nephrolithotripsy – 25. After discharge from hospital all patients had a diagnosis and correction of metabolic disorders using physical-chemical and biochemical indicators of urine and blood. To study the mineral composition and structural-textural features of urinary stones and their fragments after surgical interventions were performed: x-ray diffraction, infrared spectroscopy, polarization and electron microscopy. Was carried out following the relapse of urolithiasis: patients of the main group received pathogenetic androgen therapy as monotherapy, and patients in the control group conventional treatment (antibiotics, spasmolytic, herbal remedies. The results of therapy and follow-up care for 6 years showed a low recurrence of stone formation in patients of the main group and highest in the control. Age-related decline in androgen levels in men may be an additional factor in stone formation. Pathogenic androgen replacement therapy leads to normalization of the content of lithogenic substances in the blood and urine, as well as physico-chemical properties of urine, thereby reducing the process of stone formation.

Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development.

Science.gov (United States)

Metzler, Veronika M; de Brot, Simone; Robinson, Robert S; Jeyapalan, Jennie N; Rakha, Emad; Walton, Thomas; Gardner, David S; Lund, Emma F; Whitchurch, Jonathan; Haigh, Daisy; Lochray, Jack M; Robinson, Brian D; Allegrucci, Cinzia; Fray, Rupert G; Persson, Jenny L; Ødum, Niels; Miftakhova, Regina R; Rizvanov, Albert A; Hughes, Ieuan A; Tadokoro-Cuccaro, Rieko; Heery, David M; Rutland, Catrin S; Mongan, Nigel P

2017-08-01

The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases. Therefore the development of novel angiogenesis inhibitors has been an area of active research in oncology. A subset of the molecular processes regulating angiogenesis are well understood in the context of both early placentation and tumorigenesis. In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR are essential for normal male embryonic development, puberty and lifelong health. Defects in androgen signalling are associated with a diverse range of clinical disorders in men and women including disorders of sex development (DSD), polycystic ovary syndrome in women and many cancers. We summarize the diverse molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further delineate the role of androgen signalling in placental function and maternal and offspring health in animal models. Copyright © 2017 Elsevier Ltd. All rights reserved.

Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy

Science.gov (United States)

2017-10-01

resistant prostate cancer ; docetaxel; cabazitaxel; chemotherapy; androgen receptor splice variants; microtubule; ligand-binding domain; microtubule... receptor splice variants (AR-Vs) are associated with resistance to taxane chemotherapy in castration- resistant prostate cancer (CRPC). However, this...androgen receptor inhibitors in prostate cancer . Nat Rev Cancer . 2015;15:701–11.

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal.

Science.gov (United States)

Hildebrandt, Tom; Heywood, Ashley; Wesley, Daniel; Schulz, Kurt

2018-01-01

Synthetic androgens (i. e., anabolic-androgenic steroids) are the primary component to the majority of problematic appearance and performance enhancing drug (APED) use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc.) via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances.

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal

Directory of Open Access Journals (Sweden)

Tom Hildebrandt

2018-03-01

Full Text Available Synthetic androgens (i. e., anabolic-androgenic steroids are the primary component to the majority of problematic appearance and performance enhancing drug (APED use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc. via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances.

Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer.

Science.gov (United States)

Kashiwagi, Eiji; Ide, Hiroki; Inoue, Satoshi; Kawahara, Takashi; Zheng, Yichun; Reis, Leonardo O; Baras, Alexander S; Miyamoto, Hiroshi

2016-08-02

Cisplatin (CDDP)-based combination chemotherapy remains the mainstream treatment for advanced bladder cancer. However, its efficacy is often limited due to the development of resistance for which underlying mechanisms are poorly understood. Meanwhile, emerging evidence has indicated the involvement of androgen-mediated androgen receptor (AR) signals in bladder cancer progression. In this study, we aimed to investigate whether AR signals have an impact on sensitivity to CDDP in bladder cancer cells. UMUC3-control-short hairpin RNA (shRNA) cells with endogenous AR and AR-negative 647V/5637 cells stably expressing AR were significantly more resistant to CDDP treatment at its pharmacological concentrations, compared with UMUC3-AR-shRNA and 647V-vector/5637-vector control cells, respectively. A synthetic androgen R1881 significantly reduced CDDP sensitivity in UMUC3, 647V-AR, or 5637-AR cells, and the addition of an anti-androgen hydroxyflutamide inhibited the effect of R1881. In these AR-positive cells, R1881 treatment also induced the expression levels of NF-κB, which is known to involve CDDP resistance, and its phosphorylated form, as well as nuclear translocation of NF-κB. In CDDP-resistant bladder cancer sublines established following long-term culture with CDDP, the expression levels of AR as well as NF-κB and phospho-NF-κB were considerably elevated, compared with respective control sublines. In bladder cancer specimens, there was a strong trend to correlate between AR positivity and chemoresistance. These results suggest that AR activation correlates with CDDP resistance presumably via modulating NF-κB activity in bladder cancer cells. Targeting AR during chemotherapy may thus be a useful strategy to overcome CDDP resistance in patients with AR-positive bladder cancer.

Quality of life of lung cancer patients receiving outpatient chemotherapy

OpenAIRE

MATSUDA, AYAKO; KOBAYASHI, MIKA; SAKAKIBARA, YUMI; TAMAOKA, MEIYO; FURUIYE, MASASHI; INASE, NAOHIKO; MATSUSHIMA, EISUKE

2011-01-01

An increasing number of cancer patients receive outpatient chemotherapy as an alternative to inpatient chemotherapy. The aim of this study was to investigate whether quality of life (QOL) during outpatient chemotherapy was better than QOL prior to hospital discharge, and to explore possible related factors prior to hospital discharge that affected the QOL of lung cancer patients who received outpatient chemotherapy. Lung cancer inpatients who were scheduled for outpatient chemotherapy were as...

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy-Resistant Prostate Cancer

Science.gov (United States)

2017-10-01

treat patients with prostate cancer, over time the tumors become resistant to the drugs, leaving few treatment options. The goal of this proposal is to...interactions with the AR. 15. SUBJECT TERMS androgen receptor, prostate cancer, peptidomimetic conjugates, 16. SECURITY CLASSIFICATION OF: 17...used successfully to treat patients with prostate cancer, over time the tumors become resistant to the drugs, leaving few treatment options. The goal

ANABOLIC ANDROGENIC STEROIDS AND ADVERSE EVENTS OF THEIR APPLICATION

Directory of Open Access Journals (Sweden)

Nina Đukanović

2011-08-01

Full Text Available Anabolic androgenic steroids are synthetic compounds originating from testosterone. Their main effects are the control of development and expression of male secondary sexual characteristics, which are known as androgenic effects, and encourage muscle growth or anabolic effects. Anabolic androgenic steroids are most commonly used illegal substances. Besides these physiological effects, which are achieved using therapeutic doses of these preparations, higher doses than recommended, especially over the longer term, may be associated with the emergence of numerous adverse events. Adverse events may be registered in almost all organs and organ systems, but usually include changes in the reproductive system, skin, liver and cardiovascular system.

Effects of vitamin D supplementation on insulin sensitivity and androgen levels in vitamin-D-deficient polycystic ovary syndrome patients.

Science.gov (United States)

Karadağ, Cihan; Yoldemir, Tevfik; Yavuz, Dilek Gogas

2018-02-01

The aim of this study was to identify the effects of vitamin D supplementation on insulin sensitivity and androgen levels in vitamin-D-deficient polycystic ovary syndrome (PCOS) patients. Sixty-seven vitamin-D-deficient (25-hydroxyvitamin D [25(OH)D] levels below 20 ng/mL) PCOS patients and 54 vitamin-D-deficient non-PCOS volunteer subjects matched for age and body mass index were enrolled to this prospective study. All participants were given 50 000 IU/week cholecalciferol orally for 8 weeks and 1500 IU/day for 4 weeks. Insulin sensitivity was calculated with the Matsuda insulin sensitivity index (ISI) based on an oral glucose tolerance test. Matsuda ISI, gonadal hormones (estrogen, testosterone, androstenedione), and 25(OH)D levels were studied before and at the end of the 12th week of vitamin D load. After vitamin D supplementation, serum androstenedione levels had decreased significantly (P = 0.007) and Matsuda ISI values had increased significantly (P = 0.001) in the PCOS group but no significant changes were seen in those parameters in controls. We observed positive correlations between 25(OH)D levels and Matsuda ISI (r = 0.307; P < 0.01), and negative correlations between 25(OH)D levels and total testosterone (r = -0.306; P < 0.01) and androstenedione (r = -0.275; P < 0.01) levels in the PCOS group. Vitamin D supplementation increased insulin sensitivity and decreased androgen levels in vitamin-D-deficient women with PCOS but did not have any effect in vitamin-D-deficient non-PCOS women. These results may indicate the possible role of vitamin D in the complex pathogenesis of PCOS. © 2017 Japan Society of Obstetrics and Gynecology.

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

Science.gov (United States)

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered.

Alterations in Hydrocortisone Pharmacokinetics in a Patient With Congenital Adrenal Hyperplasia Following Bariatric Surgery.

Science.gov (United States)

Mallappa, Ashwini; Nella, Aikaterini A; Kumar, Parag; Brooks, Kristina M; Perritt, Ashley F; Ling, Alexander; Liu, Chia-Ying; Merke, Deborah P

2017-07-01

Management of adult patients with classic congenital adrenal hyperplasia (CAH) is challenging and often complicated by obesity, metabolic syndrome, and adverse cardiovascular risk. Alterations in weight can influence cortisol kinetics. A 19-year-old woman with classic CAH and morbid obesity experienced persistent elevations of androgen levels while receiving oral glucocorticoid therapy. Control of adrenal androgens was improved with continuous subcutaneous hydrocortisone infusion therapy, but obesity-related comorbidities persisted. After undergoing sleeve gastrectomy, the patient experienced dramatic weight loss, with improvement in insulin sensitivity and fatty liver in the postbariatric period. Cortisol clearance studies performed to evaluate changes in hydrocortisone dose requirements showed marked alternations in cortisol pharmacokinetics with decreases in volume of distribution and cortisol clearance, along with an increase in area under the curve for cortisol. Hydrocortisone dose was subsequently decreased 34% by 15 months after surgery. Effective control of androgen excess on this lower hydrocortisone dose was achieved and continues 27 months after surgery. This case highlights obesity-related complications of glucocorticoid replacement therapy in the management of CAH. Individual patient factors, such as fatty liver disease and insulin resistance, can have a clinically important effect on cortisol metabolism. Bariatric surgery was a safe and effective treatment of obesity in this patient with CAH and should be considered for patients with CAH and multiple obesity-related comorbidities.

Assessment of psychological responses in patients about to receive radiotherapy

International Nuclear Information System (INIS)

Karasawa, Kumiko; Horikawa, Naoshi; Kawase, Eri

2005-01-01

Radiotherapy is considered to be associated with psychological distress. We assessed the mental status, anxiety, and the factors associated with these in cancer patients about to receive radiotherapy. Hospitalized patients about to receive radiotherapy participated. Psychological status was assessed by a psychiatrist, based on interview about the type of anxiety related to cancer or radiotherapy as well as self-rating questionnaires. Eligible data were collected from 94 patients. The incidence of mental disorders was 20%. The total mood disturbance scores were significantly higher in patients with poor performance status. The most common type of anxiety regarding radiotherapy was acute adverse effect, and the predictors were palliative treatment and living alone. Mental disorders, mood disturbance, and anxiety in patients cannot be neglected in radiation oncology practice. Especially careful attention should be paid to patients with these predictive factors. (author)

Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients

Directory of Open Access Journals (Sweden)

Martin Zweifel

2017-09-01

Full Text Available CR1447 (4-hydroxytestosterone, 4-OHT binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs were seen. Two patients (17% achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA, a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo. In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day.

[Histopathological changes due to transurethural microwave thermotherapy associated with androgen deprivation therapy in patients with localized prostate cancer].

Science.gov (United States)

Jujo, Yutaka; Koshiba, Ken; Suzuki, Ryuta; Hoshiai, Osamu; Endo, Tadao; Aihara, Masahiro; Katsuta, Masayuki; Nakajo, Hirotaka

2006-03-01

The 2nd generation transurethral microwave thermotherapy (TUMT), equipped with high energy microwave generator and urethral cooling device is widely accepted as an less invasive effective modality to treat benign prostatic hyperplasia. For prostatic cancer, however, it is generally estimated as insufficient because of limitation in penetration of microwave into deep prostatic tissue. In this study, we examined histopathologic changes after androgen deprivation theraphy (ADT) and TUMT. Ten patients with localized prostate cancer underwent ADT for 3 months, and then TUMT was proceeded using Urowave (Dornier MedTech GmbH). Additional 3 months after TUMT and continued ADT, TURP in radical fashion was performed in all the patients, and all the resected chips were submitted for pathological study. Significant reduction in prostate volume was noted after NHT for 3 months from 37.4 +/- 9.6 ml to 22.0 +/- 5.6 ml. The pathological study of resected chips revealed progressive fibrotic changes without viable cancer cells in 9 of 10 patients. In 1 patient, however, some remnant of carcinomatous foci were noted in a resected chip from the middle lobe of the prostate. Although the number of patient is limited and longer follow-up is needed, the results in present series was interested and worth considering.

Cryptococcal infections in two patients receiving ibrutinib therapy for chronic lymphocytic leukemia.

Science.gov (United States)

Stankowicz, Matthew; Banaszynski, Megan; Crawford, Russell

2018-01-01

Cryptococcal infections are responsible for significant morbidity and mortality in immunocompromised patients. Reports of these infections in patients on small molecular kinase inhibitors have not been widely reported in clinical trials. We describe one case of cryptococcal meningoencephalitis and one case of cryptococcal pneumonia in two patients who were receiving ibrutinib for chronic lymphocytic leukemia. Despite different sites of cryptococcal infection, both patients had similar presentations of acute illness. Patient 1 was worked up for health care-associated pneumonia, as well as acute sinusitis prior to the diagnosis of cryptococcal meningoencephalitis. He also had a more complex past medical history than patient 2. Patient 2 developed atrial fibrillation from ibrutinib prior to admission for presumed health care-associated pneumonia. Cryptococcal antigen testing was done sooner in this patient due to patient receiving high-dose steroids for the treatment of underlying hemolytic anemia. We conclude that patients who develop acute illness while receiving ibrutinib should be considered for cryptococcal antigen testing.

Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation

Energy Technology Data Exchange (ETDEWEB)

Morooka, Nobukatsu, E-mail: amorooka@gunma-u.ac.jp [Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512 (Japan); Ueguri, Kei [Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512 (Japan); Yee, Karen Kar Lye [Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512 (Japan); Human Resources Cultivation Center, Gunma University, 1-5-1 Tenjin-cho, Kiryushi, Gunma, 376-8515 (Japan); Yanase, Toshihiko [Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka, 814-0180 (Japan); Sato, Takashi [Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512 (Japan)

2016-09-02

Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatory macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue. - Highlights: • DHT, non-aromatizable androgen suppresses Mcp-1 expression in adipocytes. • Mcp-1 transcription was negatively regulated by DHT-AR action. • DHT-AR selectively regulates Mcp-1 transcription through distinct NF-κB sites.

Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation

International Nuclear Information System (INIS)

Morooka, Nobukatsu; Ueguri, Kei; Yee, Karen Kar Lye; Yanase, Toshihiko; Sato, Takashi

2016-01-01

Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatory macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue. - Highlights: • DHT, non-aromatizable androgen suppresses Mcp-1 expression in adipocytes. • Mcp-1 transcription was negatively regulated by DHT-AR action. • DHT-AR selectively regulates Mcp-1 transcription through distinct NF-κB sites.

Non-neural androgen receptors affect sexual differentiation of brain and behaviour.

Science.gov (United States)

Monks, D A; Swift-Gallant, A

2018-02-01

Although gonadal testosterone is the principal endocrine factor that promotes masculine traits in mammals, the development of a male phenotype requires local production of both androgenic and oestrogenic signals within target tissues. Much of our knowledge concerning androgenic components of testosterone signalling in sexual differentiation comes from studies of androgen receptor (Ar) loss of function mutants. Here, we review these studies of loss of Ar function and of AR overexpression either globally or selectively in the nervous system of mice. Global and neural mutations affect socio-sexual behaviour and the neuroanatomy of these mice in a sexually differentiated manner. Some masculine traits are affected by both global and neural mutation, indicative of neural mediation, whereas other masculine traits are affected only by global mutation, indicative of an obligatory non-neural androgen target. These results support a model in which multiple sites of androgen action coordinate to produce masculine phenotypes. Furthermore, AR overexpression does not always have a phenotype opposite to that of loss of Ar function mutants, indicative of a nonlinear relationship between androgen dose and masculine phenotype in some cases. Potential mechanisms of Ar gene function in non-neural targets in producing masculine phenotypes are discussed. © 2017 British Society for Neuroendocrinology.

An Evaluation of Hepatotoxicity in Breast Cancer Patients Receiving ...

African Journals Online (AJOL)

Background: Hepatic dysfunction in the cancer unit has a significant impact on patient outcomes. The therapeutic application of anthracycline antibiotics are limited by side‑effects mainly myelosuppression, chronic cardiotoxicity, and hepatotoxicity. Aim: To assess the risk of Hepatotoxicity in breast cancer patients receiving ...

Psychological effects of androgen-deprivation therapy on men with prostate cancer and their partners.

Science.gov (United States)

Donovan, Kristine A; Walker, Lauren M; Wassersug, Richard J; Thompson, Lora M A; Robinson, John W

2015-12-15

The clinical benefits of androgen-deprivation therapy (ADT) for men with prostate cancer (PC) have been well documented and include living free from the symptoms of metastases for longer periods and improved quality of life. However, ADT comes with a host of its own serious side effects. There is considerable evidence of the adverse cardiovascular, metabolic, and musculoskeletal effects of ADT. Far less has been written about the psychological effects of ADT. This review highlights several adverse psychological effects of ADT. The authors provide evidence for the effect of ADT on men's sexual function, their partner, and their sexual relationship. Evidence of increased emotional lability and depressed mood in men who receive ADT is also presented, and the risk of depression in the patient's partner is discussed. The evidence for adverse cognitive effects with ADT is still emerging but suggests that ADT is associated with impairment in multiple cognitive domains. Finally, the available literature is reviewed on interventions to mitigate the psychological effects of ADT. Across the array of adverse effects, physical exercise appears to have the greatest potential to address the psychological effects of ADT both in men who are receiving ADT and in their partners. © 2015 American Cancer Society.

Super-Penetrant Androgen Receptor: Overcoming Enzalutamide Sensitivity in Castration-Resistant Prostate Cancer

Science.gov (United States)

2016-07-01

Prostate Cancer Research Symposium- Prostate Cancer Epigenetic Reprogramming of the Androgen Receptor in Castration Resistant Prostate Cancer , May19... cancer cells rely critically on the androgen receptor (AR) for initiation, growth and progression to castration resistant prostate cancer (CRPC...Androgen receptor, castration resistant prostate cancer , Enzalutamide , kinases. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER

Isotope and Patient Age Predict for PSA Spikes After Permanent Prostate Brachytherapy

International Nuclear Information System (INIS)

Bostancic, Chelsea; Merrick, Gregory S.; Butler, Wayne M.; Wallner, Kent E.; Allen, Zachariah; Galbreath, Robert; Lief, Jonathan; Gutman, Sarah E.

2007-01-01

Purpose: To evaluate prostate-specific antigen (PSA) spikes after permanent prostate brachytherapy in low-risk patients. Methods and Materials: The study population consisted of 164 prostate cancer patients who were part of a prospective randomized trial comparing 103 Pd and 125 I for low-risk disease. Of the 164 patients, 61 (37.2%) received short-course androgen deprivation therapy. The median follow-up was 5.4 years. On average, 11.1 post-treatment PSA measurements were obtained per patient. Biochemical disease-free survival was defined as a PSA level of ≤0.40 ng/mL after nadir. A PSA spike was defined as an increase of ≥0.2 ng/mL, followed by a durable decline to prespike levels. Multiple parameters were evaluated as predictors for a PSA spike. Results: Of the 164 patients, 44 (26.9%) developed a PSA spike. Of the 46 hormone-naive 125 I patients and 57 hormone-naive 103 Pd patients, 21 (45.7%) and 8 (14.0%) developed a PSA spike. In the hormone-naive patients, the mean time between implantation and the spike was 22.6 months and 18.7 months for 125 I and 103 Pd, respectively. In patients receiving neoadjuvant androgen deprivation therapy, the incidence of spikes was comparable between isotopes ( 125 I 28.1% and 103 Pd 20.7%). The incidence of spikes was substantially different in patients 125 I and/or <65 years of age. Differences in isotope-related spikes are most pronounced in hormone-naive patients

Positron tomographic assessment of androgen receptors in prostatic carcinoma

International Nuclear Information System (INIS)

Dehdashti, Farrokh; Siegel, Barry A.; Welch, Michael J.; Picus, Joel; Michalski, Jeff M.; Dence, Carmen S.; Katzenellenbogen, John A.

2005-01-01

The purpose of this study was to evaluate the feasibility of androgen receptor (AR) imaging with 16β-[ 18 F]fluoro-5α-dihydrotestosterone (FDHT) by positron emission tomography (PET) and to assess the binding selectivity of FDHT to AR in patients with prostate cancer. Twenty men (age range 56-87 years) with advanced prostate cancer were studied. All except one had metastatic disease confirmed by biopsy and/or radiological studies. One patient who had radiological findings suggesting a single hepatic metastasis was found to have focal fatty infiltration on biopsy obtained after FDHT-PET and was excluded from further data analysis. FDHT uptake was assessed semiquantitatively by determination of the standardized uptake value (SUV) and tumor-to-muscle ratio (T/M). Additionally, to assess the AR binding selectivity of FDHT, patients with one or more foci of abnormally increased FDHT accumulation were studied after administration of an AR antagonist (flutamide). Conventional imaging demonstrated innumerable lesions in two patients and 43 lesions in the remaining 17 patients with advanced prostate cancer. FDHT-PET was positive in 12 of 19 patients (sensitivity of 63%), including the two patients with innumerable lesions. FDHT-PET detected 24 of 28 known lesions (86%) in the remaining ten patients. In addition, FDHT-PET detected 17 unsuspected lesions in five of these ten patients. All 12 patients with positive FDHT-PET underwent a repeat PET study after receiving flutamide for 1 day (250 mg t.i.d.). In all of these patients, there was a decrease in tumor FDHT uptake after flutamide; the mean (± standard deviation) SUV and T/M decreased from 7.0±4.7 and 6.9±3.9, respectively, to 3.0±1.5 and 3.0±1.6, respectively (p=0.002). The mean PSA in patients with positive FDHT-PET was significantly higher than that in patients with negative FDHT-PET (p=0.006). Our results document the feasibility of PET imaging of prostate cancer with FDHT and suggest that tumor uptake of FDHT

Impact of Androgen and Dietary Advanced Glycation End Products on Female Rat Liver

Directory of Open Access Journals (Sweden)

Eleni Palioura

2015-09-01

Full Text Available Background/Aims: Advanced glycation end products (AGEs have been related to a wide range of liver disorders including hyperandrogenic states such as the Polycystic Ovary Syndrome (PCOS. The aim of the present study is to evaluate the potential impact of dietary glycotoxins exposure and androgen excess on hepatic histology and biochemistry in an androgenized female rat model. Methods: The study population consisted of 80 female Wistar rats, divided in 3 groups, a group of prepubertal (Group A, n=30 and adult rats (Group B, n=20 that were androgenized via subcutaneous implantation of dihydrotestosterone-containing pellets as well as a group of adult non-androgenized rodents (Group C, n=30. All groups were randomly assigned either to a high-AGE or low-AGE diet for 3 months. Results: Rats fed with a high-AGE diet exhibited significantly elevated levels of gamma-glutamyl transferase (γGT (p≤0.0002 and indices of AGE immunostaining in liver tissue (pper se constitutes an aggravating factor as demonstrated by the elevated γGT levels in adult androgenized animals compared to non-androgenized, independent of diet content (p=0.0002 and by the elevated AST and alanine aminotransferase (ALT levels in low-AGE subgroups (adult androgenized vs. non-androgenized, p=0.0002 followed by increased immunohistochemical AGE deposition in hepatocytes of the latter categories (p=0.0007. Conclusion: The present study suggests that androgens and glycotoxins may contribute synergistically to distort hepatic physiology and function as observed in hyperandrogenic conditions.

National Trends and Predictors of Androgen Deprivation Therapy Use in Low-Risk Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Yang, David D. [Harvard Medical School, Boston, Massachusetts (United States); Muralidhar, Vinayak [Department of Medicine, Harvard Medical School, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Mahal, Brandon A. [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Labe, Shelby A.; Nezolosky, Michelle D.; Vastola, Marie E.; King, Martin T.; Martin, Neil E.; Orio, Peter F. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Choueiri, Toni K. [Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Trinh, Quoc-Dien [Division of Urological Surgery, Harvard Medical School, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Spratt, Daniel E. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); University of Michigan, Ann Arbor, Michigan (United States); Hoffman, Karen E. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Feng, Felix Y. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); Departments of Urology & Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California (United States); and others

2017-06-01

Purpose: Androgen deprivation therapy (ADT) is not recommended for low-risk prostate cancer because of its lack of benefit and potential for harm. We evaluated the incidence and predictors of ADT use in low-risk disease. Methods and Materials: Using the National Cancer Database, we identified 197,957 patients with low-risk prostate cancer (Gleason score of 3 + 3 = 6, prostate-specific antigen level <10 ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information. We used multiple logistic regression to evaluate predictors of ADT use and Cox regression to examine its association with all-cause mortality. Results: Overall ADT use decreased from 17.6% in 2004 to 3.5% in 2012. In 2012, 11.5% of low-risk brachytherapy patients and 7.6% of external beam radiation therapy patients received ADT. Among 82,352 irradiation-managed patients, predictors of ADT use included treatment in a community versus academic cancer program (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.50-1.71; P<.001; incidence, 14.0% vs 6.0% in 2012); treatment in the South (AOR, 1.51), Midwest (AOR, 1.81), or Northeast (AOR, 1.90) versus West (P<.001); and brachytherapy use versus external beam radiation therapy (AOR, 1.32; 95% CI, 1.27-1.37; P<.001). Among 25,196 patients who did not receive local therapy, predictors of primary ADT use included a Charlson-Deyo comorbidity score of ≥2 versus 0 (AOR, 1.42; 95% CI, 1.06-1.91; P=.018); treatment in a community versus academic cancer program (AOR, 1.61; 95% CI, 1.37-1.90; P<.001); and treatment in the South (AOR, 1.26), Midwest (AOR, 1.52), or Northeast (AOR, 1.28) versus West (P≤.008). Primary ADT use was associated with increased all-cause mortality in patients who did not receive local therapy (adjusted hazard ratio, 1.28; 95% CI, 1.14-1.43; P<.001) after adjustment for age and comorbidity. Conclusions: ADT use in low-risk prostate cancer has declined nationally but may remain an issue

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

Science.gov (United States)

Ferraldeschi, R; Welti, J; Luo, J; Attard, G; de Bono, JS

2015-01-01

Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway. PMID:24837363

Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1

OpenAIRE

Lin, Hui-Ping; Lin, Ching-Yu; Huo, Chieh; Hsiao, Ping-Hsuan; Su, Liang-Cheng; Jiang, Shih Sheng; Chan, Tzu-Min; Chang, Chung-Ho; Chen, Li-Tzong; Kung, Hsing-Jien; Wang, Horng-Dar; Chuu, Chih-Pin

2015-01-01

Prostate cancer (PCa) patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant prostate cancer (CRPC) within 1?3 years. Treatment with caffeic acid phenethyl ester (CAPE) suppressed cell survival and proliferation via induction of G1 or G2/M cell cycle arrest in LNCaP 104-R1, DU-145, 22Rv1, and C4?2 CRPC cells. CAPE treatment also inhibited soft agar colony formation and retarded nude mice xenograft growth of LNCaP 104-R1 cells. We identified that CAP...

ANDROGEN REPLACEMENT THERAPY IN POSTMENOPAUSE

Directory of Open Access Journals (Sweden)

Helena Meden Vrtovec

2008-12-01

Scientific studies and clinical experiences have not provided until now the answers to thequestion: »Whom to treat, when, why and for how long should androgens be used for HRTin postmenopausal women?«

Out-of-hospital mortality among patients receiving methadone for noncancer pain.

Science.gov (United States)

Ray, Wayne A; Chung, Cecilia P; Murray, Katherine T; Cooper, William O; Hall, Kathi; Stein, C Michael

2015-03-01

Growing methadone use in pain management has raised concerns regarding its safety relative to other long-acting opioids. Methadone hydrochloride may increase the risk for lethal respiratory depression related to accidental overdose and life-threatening ventricular arrhythmias. To compare the risk of out-of-hospital death in patients receiving methadone for noncancer pain with that in comparable patients receiving sustained-release (SR) morphine sulfate. A retrospective cohort study was conducted using Tennessee Medicaid records from 1997 through 2009. The cohort included patients receiving morphine SR or methadone who were aged 30 to 74 years, did not have cancer or another life-threatening illness, and were not in a hospital or nursing home. At cohort entry, 32 742 and 6014 patients had filled a prescription for morphine SR or methadone, respectively. The patients' median age was 48 years, 57.9% were female, and comparable proportions had received cardiovascular, psychotropic, and other musculoskeletal medications. Nearly 90% of the patients received the opioid for back pain or other musculoskeletal pain. The median doses prescribed for morphine SR and methadone were 90 mg/d and 40 mg/d, respectively. The primary study end point was out-of-hospital mortality, given that opioid-related deaths typically occur outside the hospital. There were 477 deaths during 28 699 person-years of follow-up (ie, 166 deaths per 10 000 person-years). After control for study covariates, patients receiving methadone had a 46% increased risk of death during the follow-up period, with an adjusted hazard ratio (HR) of 1.46 (95% CI, 1.17-1.83; P Methadone doses of 20 mg/d or less, the lowest dose quartile, were associated with an increased risk of death (HR, 1.59; 95% CI, 1.01-2.51, P = .046) relative to a comparable dose of morphine SR (methadone in this retrospective cohort study, even for low doses, supports recommendations that it should not be a drug of first choice for

Abnormal P-53 suppressor gene expression predicts for a poorer outcome in patients with locally advanced adenocarcinoma of the prostate treated by external beam radiation therapy with or without pre-radiation androgen ablation: results based on RTOG study 86-10

International Nuclear Information System (INIS)

Lawton, Colleen A.; Grignon, David; Caplan, Richard; Sarkar, Fazlul; Forman, Jeffrey; Mesic, John; Fu, Karen K.; Abrams, Ross

1995-01-01

Purpose/Objective: The purpose of this study is to establish the effect of the abnormal expression of the P-53 suppressor gene on the results of locally advanced adenocarcinoma of the prostate treated with radiation therapy with or without pre-radiation therapy androgen ablation. Materials and Methods: Patients evaluated were part of a RTOG phase III multi-institutional trial. This trial assessed the value of pre-radiation therapy androgen ablation on patients with locally advanced disease (bulky stage B and stage C). Of the 471 patients registered, pre-treatment pathological material was available for 129 patients. P-53 status was determined immunohistochemically utilizing a commercially available antibody (D07). Clinical endpoints evaluated were overall survival and development of metastases. Results: Twenty-three of the 129 patients had abnormal expression of the P-53 suppressor gene. Presence of this abnormal expression significantly correlated with lower overall survival (p=0.03) and the development of distant metastases (p=0.03). Abnormal expression of the P-53 gene was an independent prognostic indicator when evaluated against clinical stage and Gleason score. Conclusion: This data from patients entered on a phase III multi-institutional, randomized clinical trial shows that abnormal P-53 suppressor gene expression as determined immunohistochemically is an independent predictor of poorer survival and the development of distant metastases in patients with locally advanced adenocarcinoma of the prostate treated with radiation therapy with or without pre-radiation therapy androgen ablation

Fetal programming of adrenal androgen excess: lessons from a nonhuman primate model of polycystic ovary syndrome.

Science.gov (United States)

Abbott, David H; Zhou, Rao; Bird, Ian M; Dumesic, Daniel A; Conley, Alan J

2008-01-01

Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of dehydroepiandrosterone sulfate (DHEAS), typical of polycystic ovary syndrome (PCOS) women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in controls. Pioglitazone treatment, however, diminishes circulating DHEAS responses to ACTH in both prenatally androgenized and control female monkeys, while increasing the 17-hydroxyprogesterone response and reducing the DHEA to 17-hydroxyprogesterone ratio. Since 60-min post-ACTH serum values for 17-hydroxyprogesterone correlate negatively with basal serum insulin levels (all female monkeys on pioglitazone and placebo treatment combined), while similar DHEAS values correlate positively with basal serum insulin levels, circulating insulin levels may preferentially support adrenal androgen biosynthesis in both prenatally androgenized and control female rhesus monkeys. Overall, our findings suggest that differentiation of the monkey adrenal cortex in a hyperandrogenic fetal environment may permanently upregulate adult adrenal androgen biosynthesis through specific elevation of 17,20-lyase activity in the zona fasciculata-reticularis. As adult prenatally androgenized female rhesus monkeys closely emulate PCOS-like symptoms, excess fetal androgen programming may contribute to adult adrenal androgen excess in women with PCOS.

Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

National Research Council Canada - National Science Library

Wang, Zhou

2001-01-01

.... The dietary influence on ventral prostate weight does not seem to involve androgen action axis because dietary components did not influence the expression of several androgen-response genes, serum testosterone...

Effect of Cuscuta reflexa Roxb on androgen-induced alopecia.

Science.gov (United States)

Pandit, Shweta; Chauhan, Nagendra Singh; Dixit, V K

2008-09-01

Alopecia is a psychologically distressing condition. Androgenetic alopecia, which affects millions of men and women, is an androgen-driven disorder. Here, Cuscuta reflexa Roxb is evaluated for hair growth activity in androgen-induced alopecia. Petroleum ether extract of C. reflexa was studied for its hair growth-promoting activity. Alopecia was induced in albino mice by testosterone administration for 20 days. Its inhibition by simultaneous administration of extract was evaluated using follicular density, anagen/telogen ratio, and microscopic observation of skin sections. To investigate the mechanism of observed activity, in vitro experiments were performed to study the effect of extract and its major component on activity of 5alpha-reductase enzyme. Petroleum ether extract of C. reflexa exhibited promising hair growth-promoting activity as reflected from follicular density, anagen/telogen ratio, and skin sections. Inhibition of 5alpha-reductase activity by extract and isolate suggest that the extract reversed androgen-induced alopecia by inhibiting conversion of testosterone to dihydrotestosterone. The petroleum ether extract of C. reflexa and its isolate is useful in treatment of androgen-induced alopecia by inhibiting the enzyme 5alpha-reductase.

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

Directory of Open Access Journals (Sweden)

Alfonso Urbanucci

2017-06-01

Full Text Available Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4 have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC. Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC. We show that the deregulation of androgen receptor (AR expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10 for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Update of monotherapy trials with the new anti-androgen, Casodex (ICI 176,334). International Casodex Investigators

DEFF Research Database (Denmark)

Iversen, P

1994-01-01

Casodex (ICI 176,334) is a non-steroidal anti-androgen, which has a half-life compatible with once-daily oral dosing. In an open, phase II study on 267 patients given Casodex, 50 mg/day, an overall objective response (i.e. partial regression) was seen in 55.5% of patients (146 of 263) with a furt...

Fosaprepitant-induced phlebitis: a focus on patients receiving doxorubicin/cyclophosphamide therapy.

Science.gov (United States)

Leal, A D; Kadakia, K C; Looker, S; Hilger, C; Sorgatz, K; Anderson, K; Jacobson, A; Grendahl, D; Seisler, D; Hobday, T; Loprinzi, Charles L

2014-05-01

The purpose of this study was to investigate the incidence of fosaprepitant-associated infusion site adverse events (ISAEs) among a cohort of breast cancer patients receiving doxorubicin/cyclophosphamide (AC) chemotherapy. A retrospective review of electronic medical record (EMR) data was performed for all patients who were initiated on AC from January 2011 to April 2012. Data collected included baseline demographics, antiemetic regimen, documentation of ISAEs, and type of intravenous (IV) access. Descriptive statistics (mean and standard deviation or percentages) were summarized overall, by type of IV access and initial antiemetic given. Among the 148 patients included in this analysis, 98 initially received fosaprepitant and 44 received aprepitant. The incidence of ISAEs associated with fosaprepitant administration was 34.7 % (n=34), while the incidence of aprepitant-associated ISAEs was 2.3 % (n=1). All ISAEs were associated with peripheral IV access. The most commonly reported ISAEs were infusion site pain (n=26), erythema (n=22), swelling (n=12), superficial thrombosis (n=8), infusion site hives (n=5), and phlebitis/thrombophlebitis (n=5). Twenty-six patients experienced more than one type of ISAE. The incidence and severity of ISAEs associated with fosaprepitant administration among a group of patients receiving AC chemotherapy are significant and appreciably higher than what has been previously reported.

Androgens and the ageing male

DEFF Research Database (Denmark)

Juul, Anders; Skakkebaek, Niels E

2002-01-01

Hypogonadal men share a variety of signs and symptoms such as decreased muscle mass, osteopoenia, increased fat mass, fatigue, decreased libido and cognitive dysfunctions. Controlled trials have demonstrated favourable effects of androgen substitution therapy on these signs and symptoms in men...... 'andropause' has been suggested. However, testosterone levels show no or only modest variation with age in men; with large prospective studies suggesting a maximal decline of total testosterone of 1.6% per year. Thus, in contrast to the sudden arrest of gonadal activity in females around menopause, men do...... not have an andropause. As large placebo-controlled studies of androgen treatment in elderly males are lacking, proper risk assessment of adverse effects such as prostate cancer following testosterone treatment in elderly males is completely lacking. In the future, testosterone therapy may prove beneficial...

Characterizations of Factors Affecting Androgen Receptor Transcriptional Regulation in Prostate Cancer

National Research Council Canada - National Science Library

Garabedian, Michael

2003-01-01

.... Expression of ART-27 in LNCaP cells, an androgen-dependent prostate cancer cell line, reduces androgen-mediated cellular proliferation, suggesting that ART-27 plays a role in suppressing cell growth...

Androgen and androgen metabolite levels in serum and urine of East African chimpanzees (Pan troglodytes schweinfurthii): comparison of EIA and LC-MS analyses.

Science.gov (United States)

Preis, Anna; Mugisha, Lawrence; Hauser, Barbara; Weltring, Anja; Deschner, Tobias

2011-12-01

The primary male androgen testosterone (T) is often used as an endocrinological marker to investigate androgen-behaviour interactions in males. In chimpanzees and bonobos, studies investigating the relationship between T levels and dominance rank or aggressive behaviour have revealed contradictory results. The immunoassays used in these studies were originally developed for the measurement of steroids in serum. Their application to non-invasively collected samples, however, can lead to methodological problems due to cross-reacting metabolites, which might occur in urine or faeces but not in blood. The overall aim of this study, therefore, is to clarify whether a T enzyme immunoassay (EIA) is an applicable method to monitor testicular function in adult male chimpanzees. To estimate the impact of cross-reacting androgens on the used T EIA, we compared the results of an EIA measurement with a set of androgen metabolite levels measured by LC-MS. In urine from male chimpanzees, cross-reactivities appear to exist mainly with T and its exclusive metabolites, 5α-dihydrotestosterone (5α-DHT) and 5α-androstanediol (androstanediol). Both urinary and serum T levels of male chimpanzees were significantly higher than female T levels when measured with the T EIA, indicating a reliable measurement of testicular androgens and their exclusive metabolites with the used EIA. In urine from female chimpanzees, the comparison between LC-MS and T EIA results indicated a higher impact of cross-reactions with adrenal androgen metabolites. Therefore, the investigation of urinary T levels in female chimpanzees with a T EIA seems to be problematic. Overall our results show that a T EIA can be a reliable method to monitor testicular function in male chimpanzee urine and that LC-MS is a valuable tool for the validation of immunoassays. Copyright © 2011 Elsevier Inc. All rights reserved.

Sugammadex Improves Neuromuscular Function in Patients Receiving Perioperative Steroids.

Science.gov (United States)

Ozer, A B; Bolat, E; Erhan, O L; Kilinc, M; Demirel, I; Toprak, G Caglar

2018-02-01

Sugammadex has steroid-encapsulating effect. This study was undertaken to assess whether the clinical efficacy of sugammadex was altered by the administration of steroids. Sixty patients between 18 and 60 years of age with the American Society of Anesthesiologists I-IV and undergoing elective direct laryngoscopy/biopsy were included in this study. Patients were assigned to two groups based on the intraoperative steroid use: those who received steroid (Group S) and who did not (Group C). After standard general anesthesia, patients were monitored with the train of four (TOF) monitoring. The preferred steroid and its dose, timing of steroid administration, and TOF value before and after sugammadex as well as the time to recovery (TOF of 0.9) were recorded. SPSS software version 17.0 was used for statistical analysis. There is no statistically significant difference between groups in terms of age, gender, preoperative medication use, and TOF ratio just before administering sugammadex. The reached time to TOF 0.9 after sugammadex administration was significantly shorter in Group S than Group C (P sugammadex as well as the dose of sugammadex in those who received prednisolone; time to TOF 0.9 was higher in prednisolone receivers as compared to dexamethasone receivers (P sugammadex was found, in contrast with what one expect. Further studies are required to determine the cause of this effect which is probably due to a potential interaction between sugammadex and steroids.

ASSESSMENT OF IN VITRO ANDROGENIC ACTIVITY IN KRAFT MILL EFFLUENT

Science.gov (United States)

Detection of In Vitro Androgenic Activity in Feedlot Effluent. Lambright, CS 1 , Guillette, LJ, Jr.2, Gray, LE, Jr.1 , 1USEPA, NHEERL, RTP, NC, 2 University of Florida, Dept. of Zoology, Gainesville FLRecent studies have shown the presence of androgenic activity in water...

Estrogens and Androgens in Skeletal Physiology and Pathophysiology

OpenAIRE

Almeida, Maria; Laurent, Michaël R.; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A.; Bouillon, Roger; Vanderschueren, Dirk; Manolagas, Stavros C.

2016-01-01

Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably t...

Androgenic anabolic steroid use among male adolescents in Falkenberg.

Science.gov (United States)

Nilsson, S

1995-01-01

Recent reports show that androgenic anabolic steroids are used by many teenagers, not as a deliberate attempt to give them strength, better athletic performance, etc., but to improve their looks. The so-called macho cult among young boys tempts them into using androgenic anabolic steroids to give them bigger muscles and a more powerful appearance. This study was undertaken to investigate the prevalence of androgenic anabolic steroid use among teenagers in a small town and to create a platform for future work with the aim of decreasing the misuse of these drugs. In Falkenberg, a town in the county of Halland in the west of Sweden, the pupils at two high schools were investigated by means of an anonymous multiple-choice questionnaire. A total of 1383 students (688 males and 695 females) aged 14-19 years participated in the study, giving a participation rate of 96%. The number of answers completed was 99%. The use of androgenic anabolic steroids is a reality among male teenagers in Falkenberg, with 5.8% of them using the drugs. Among 15- to 16-year-old boys misuse of these drugs is as high as 10%, and of these 50% (5.0% of total) also inject ampoules of the drugs. This prevalence is alarming since the adverse effects of androgenic anabolic steroids are more serious in teenagers. Serious action must be taken to inform teenagers of the consequences of misusing drugs.

Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation

Directory of Open Access Journals (Sweden)

Julia Lipianskaya

2014-08-01

Full Text Available Most prostate cancers (PCas are classified as acinar type (conventional adenocarcinoma which are composed of tumor cells with luminal differentiation including the expression of androgen receptor (AR and prostate-specific antigen (PSA. There are also scattered neuroendocrine (NE cells in every case of adenocarcinoma. The NE cells are quiesecent, do not express AR or PSA, and their function remains unclear. We have demonstrated that IL8-CXCR2-P53 pathway provides a growth-inhibitory signal and keeps the NE cells in benign prostate and adenocarcinoma quiescent. Interestingly, some patients with a history of adenocarcinoma recur with small cell neuroendocrine carcinoma (SCNC after hormonal therapy, and such tumors are composed of pure NE cells that are highly proliferative and aggressive, due to P53 mutation and inactivation of the IL8-CXCR2-P53 pathway. The incidence of SCNC will likely increase due to the widespread use of novel drugs that further inhibit AR function or intratumoral androgen synthesis. A phase II trial has demonstrated that platinum-based chemotherapy may be useful for such therapy-induced tumors.

Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery.

Science.gov (United States)

Segal, Scott; Narayanan, Ramesh; Dalton, James T

2006-04-01

Selective androgen receptor modulators (SARMS) bind to the androgen receptor and demonstrate anabolic activity in a variety of tissues; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents are able to induce bone and muscle growth, as well as shrinking the prostate. The potential of SARMS is to maximise the positive attributes of steroidal androgens as well as minimising negative effects, thus providing therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, end-stage renal disease, osteoporosis, frailty and hypogonadism. This review summarises androgen physiology, the current status of the R&D of SARMS and potential therapeutic indications for this emerging class of drugs.

Androgenic Hormones In Relation To Parameters of the Metabolic Syndrome in male patients

International Nuclear Information System (INIS)

Shousha, M. A.; Soliman, S. E.; Semna, S. G.

2012-12-01

Back ground and aim of the work :The numerous deleterious effects of metabolic syndrome are being investigated throughout the medical community. Hypo-androgenomes in men is associated with features of the metabolic syndrome, even it may predict the metabolic syndrome, but the association with the metabolic syndrome it self using an accepted definition has not been described. A group 40 men defined as metabolic syndrome were assessed to investigate the relationship between androgenic hormones and parameters of the metabolic syndrome. (Author)

Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A treatment

Science.gov (United States)

We sought to determine whether lutein supplementation will slow visual function decline in patients with retinitis pigmentosa receiving vitamin A. DESIGN: Randomized, controlled, double-masked trial of 225 nonsmoking patients, aged 18 to 60 years, evaluated over a 4-year interval. Patients received ...

A phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate cancer

International Nuclear Information System (INIS)

Newton, Robert U; Taaffe, Dennis R; Spry, Nigel; Gardiner, Robert A; Levin, Gregory; Wall, Bradley; Joseph, David; Chambers, Suzanne K; Galvão, Daniel A

2009-01-01

Androgen deprivation therapy (ADT) is accompanied by a number of adverse side effects including reduced bone mass and increased risk for fracture, reduced lean mass and muscle strength, mood disturbance and increased fat mass compromising physical functioning, independence, and quality of life. The purpose of this investigation is to examine the effects of long term exercise on reversing musculoskeletal-related side effects, and cardiovascular and diabetes risk factors in men receiving androgen deprivation for their prostate cancer. Specifically, we aim to investigate the effects of a 12-month exercise program designed to load the musculoskeletal system and reduce cardiovascular and diabetes disease progression on the following primary endpoints: 1) bone mineral density; 2) cardiorespiratory function and maximal oxygen capacity; 3) body composition (lean mass and fat mass); 4) blood pressure and cardiovascular function; 5) lipids and glycemic control; and 6) quality of life and psychological distress. Multi-site randomized controlled trial of 195 men (65 subjects per arm) undergoing treatment for prostate cancer involving ADT in the cities of Perth and Brisbane in Australia. Participants will be randomized to (1) resistance/impact loading exercise, (2) resistance/cardiovascular exercise groups and (3) usual care/delayed exercise. Participants will then undergo progressive training for 12 months. Measurements for primary and secondary endpoints will take place at baseline, 6 and 12 months (end of the intervention). The principal outcome of this project will be the determination of the strength of effect of exercise on the well established musculoskeletal, cardiovascular and insulin metabolism side effects of androgen deprivation in prostate cancer patients. As this project is much longer term than previous investigations in the area of exercise and cancer, we will gain knowledge as to the continuing effects of exercise in this patient population specifically

Androgen levels in women with various forms of ovarian dysfunction : Associations with cardiometabolic features

NARCIS (Netherlands)

Daan, N. M P; Jaspers, L.; Koster, M. P H; Broekmans, F. J M; De Rijke, Y. B.; Franco, O. H.; Laven, J. S E; Kavousi, M.; Fauser, B. C J M

2015-01-01

STUDY QUESTION Are differences in androgen levels among women with various forms of ovarian dysfunction associated with cardiometabolic abnormalities? SUMMARY ANSWER Androgen levels differed substantially between women with and without ovarian dysfunction, and increased androgen levels were

Steroid Androgen Exposure during Development Has No Effect on Reproductive Physiology of Biomphalaria glabrata.

Directory of Open Access Journals (Sweden)

Satwant Kaur

Full Text Available Gastropod mollusks have been proposed as alternative models for male reproductive toxicity testing, due to similarities in their reproductive anatomy compared to mammals, together with evidence that endocrine disrupting chemicals can cause effects in some mollusks analogous to those seen in mammals. To test this hypothesis, we used the freshwater pulmonate snail, Biomphalaria glabrata, for which various genetic tools and a draft genome have recently become available, to investigate the effects of two steroid androgens on the development of mollusk secondary sexual organs. Here we present the results of exposures to two potent androgens, the vertebrate steroid; 5α-dihydrotestosterone (DHT and the pharmaceutical anabolic steroid; 17α-methyltestosterone (MT, under continuous flow-through conditions throughout embryonic development and up to sexual maturity. Secondary sexual gland morphology, histopathology and differential gene expression analysis were used to determine whether steroid androgens stimulated or inhibited organ development. No significant differences between tissues from control and exposed snails were identified, suggesting that these androgens elicited no biologically detectable response normally associated with exposure to androgens in vertebrate model systems. Identifying no effect of androgens in this mollusk is significant, not only in the context of the suitability of mollusks as alternative model organisms for testing vertebrate androgen receptor agonists but also, if applicable to other similar mollusks, in terms of the likely impacts of androgens and anti-androgenic pollutants present in the aquatic environment.

PCA3 Silencing Sensitizes Prostate Cancer Cells to Enzalutamide-mediated Androgen Receptor Blockade.

Science.gov (United States)

Özgür, Emre; Celik, Ayca Iribas; Darendeliler, Emin; Gezer, Ugur

2017-07-01

Prostate cancer (PCa) is an androgen-dependent disease. Novel anti-androgens (i.e. enzalutamide) have recently been developed for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Evidence is accumulating that prostate cancer antigen 3 (PCA3) is involved in androgen receptor (AR) signaling. Here, in combination with enzalutamide-mediated AR blockade, we investigated the effect of PCA3 targeting on the viability of PCa cells. In hormone-sensitive LNCaP cells, AR-overexpressing LNCaP-AR + cells and VCaP cells (representing CRPC), PCA3 was silenced using siRNA oligonucleotides. Gene expression and cell viability was assessed in PCA3-silenced and/or AR-blocked cells. PCA3 targeting reduced the expression of AR-related genes (i.e. prostate-specific antigen (PSA) and prostate-specific transcript 1 (non-protein coding) (PCGEM1)) and potentiated the effect of enzalutamide. Proliferation of PCa cells was suppressed upon PCA3 silencing with a greater effect in LNCaP-AR + cells. Furthermore, PCA3 silencing sensitized PCa cells to enzalutamide-induced loss of cell growth. PCA3, as a therapeutic target in PCa, might be used to potentiate AR antagonists. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Malignancies.

Science.gov (United States)

Varughese, Tilly; Taur, Ying; Cohen, Nina; Palomba, M Lia; Seo, Susan K; Hohl, Tobias M; Redelman-Sidi, Gil

2018-03-02

Ibrutinib is a Bruton's tyrosine kinase inhibitor that is used for the treatment of lymphoid malignancies, including chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia and mantle cell lymphoma (MCL). Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. We reviewed the electronic medical records of patients with lymphoid malignancies at Memorial Sloan Kettering Cancer Center who received ibrutinib during a five-year period from January 1, 2012 to December 31, 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by univariate and multivariate analyses. 378 patients with lymphoid malignancies who received ibrutinib were analyzed. The most common underlying malignancies were CLL and MCL. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Of these, 23 (53.5%) developed invasive bacterial infections, and 16 (37.2%) developed invasive fungal infections (IFI). The majority of those who developed IFI on ibrutinib therapy (62.5%) lacked classical clinical risk factors for fungal infection (i.e., neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in six of the 43 patients (14%). Patients with lymphoid malignancies receiving ibrutinib treatment are at risk for serious infections, including IFI.

Fetal programming of adrenal androgen excess: lessons from a nonhuman primate model of polycystic ovary syndrome

OpenAIRE

Abbott, David H; Zhou, Rao; Bird, Ian M; Dumesic, Daniel A; Conley, Alan J

2008-01-01

Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of DHEAS, typical of PCOS women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in co...

Enzalutamide for the Treatment of Androgen Receptor-Expressing Triple-Negative Breast Cancer.

Science.gov (United States)

Traina, Tiffany A; Miller, Kathy; Yardley, Denise A; Eakle, Janice; Schwartzberg, Lee S; O'Shaughnessy, Joyce; Gradishar, William; Schmid, Peter; Winer, Eric; Kelly, Catherine; Nanda, Rita; Gucalp, Ayca; Awada, Ahmad; Garcia-Estevez, Laura; Trudeau, Maureen E; Steinberg, Joyce; Uppal, Hirdesh; Tudor, Iulia Cristina; Peterson, Amy; Cortes, Javier

2018-03-20

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.

The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

International Nuclear Information System (INIS)

Chuu, Chih-pin; Chen, Rou-Yu; Hiipakka, Richard A.; Kokontis, John M.; Warner, Karen V.; Xiang, Jialing; Liao, Shutsung

2007-01-01

T0901317 is a potent non-steroidal synthetic liver X receptor (LXR) agonist. T0901317 blocked androgenic stimulation of the proliferation of androgen-dependent LNCaP 104-S cells and androgenic suppression of the proliferation of androgen-independent LNCaP 104-R2 cells, inhibited the transcriptional activation of an androgen-dependent reporter gene by androgen, and suppressed gene and protein expression of prostate specific antigen (PSA), a target gene of androgen receptor (AR) without affecting gene and protein expression of AR. T0901317 also inhibited binding of a radiolabeled androgen to AR, but inhibition was much weaker compared to the effect of the antiandrogens, bicalutamide and hydroxyflutamide. The LXR agonist T0901317, therefore, acts as an antiandrogen in human prostate cancer cells

Antioxidants inhibition of high plasma androgenic markers in the pathogenesis of ethylene glycol (EG)-induced nephrolithiasis in Wistar rats.

Science.gov (United States)

Naghii, Mohammad Reza; Mofid, Mahmood; Hedayati, Mehdi; Khalagi, Kazem

2014-04-01

The association between serum gonadal steroids and urolithiasis in males received only limited attention. Calcium oxalate urolithiasis is induced by administration of ethylene glycol in drinking water. It appears that the administration of natural antioxidants has been used to protect against nephrolithiasis in human and experimental animals. The purpose is to study the potential role of antioxidants as inhibitors of high plasma androgenic markers or hyperandrogenicity in the pathogenesis of ethylene glycol-induced nephrolithiasis in Wistar rats. Male Wistar rats were studied in 4-week period. Group 1 (control) was fed a standard commercial diet. Group 2 received the same diet with 0.5 % of ethylene glycol. Group 3 received EG plus the diet and water added with antioxidant nutrients and lime juice as the dietary source of citrate. Group 4 and Group 5 were treated similar to Group 2 and Group 3 with 0.75 % of ethylene glycol. For antioxidant supplementation, the standard diet enriched with 4,000.0 μg vitamin E and 1,500.0 IU vitamin A for each rat per day added to the diet once a week, and provided daily with 5.0 mg vitamin C, 400.0 μg vitamin B6, 20.0 μg selenium, 12.0 mg zinc, and 2.0 mg boron for each rat per day in their drinking water. After treatment period, collection of blood was performed and kidneys were removed and used for histopathological examination. The results based on various assays, measuring size of crystal deposition, and histological examinations showed that high concentration of androgens acts as promoter for the formation of renal calculi due to ethylene glycol consumption and the inhibitory role of antioxidant complex in the formation of renal calculi disease. Data revealed that the size and the mean number of crystal deposits determined in EG 0.75 % treated groups (G4) were significantly higher than the EG-treated groups, added with antioxidant nutrients and lime juice (G5). The mean concentration of androgens in Group 4 increased after

Oral Cryotherapy for Preventing Oral Mucositis in Patients Receiving Cancer Treatment.

Science.gov (United States)

Riley, Philip; McCabe, Martin G; Glenny, Anne-Marie

2016-10-01

In patients receiving treatment for cancer, does oral cryotherapy prevent oral mucositis? Oral cryotherapy is effective for the prevention of oral mucositis in adults receiving fluorouracil-based chemotherapy for solid cancers, and for the prevention of severe oral mucositis in adults receiving high-dose melphalan-based chemotherapy before hematopoietic stem cell transplantation (HSCT).

Developmental programming by androgen affects the circadian timing system in female mice.

Science.gov (United States)

Mereness, Amanda L; Murphy, Zachary C; Sellix, Michael T

2015-04-01

Circadian clocks play essential roles in the timing of events in the mammalian hypothalamo-pituitary-ovarian (HPO) axis. The molecular oscillator driving these rhythms has been localized to tissues of the HPO axis. It has been suggested that synchrony among these oscillators is a feature of normal reproductive function. The impact of fertility disorders on clock function and the role of the clock in the etiology of endocrine pathology remain unknown. Polycystic ovarian syndrome (PCOS) is a particularly devastating fertility disorder, affecting 5%-10% of women at childbearing age with features including a polycystic ovary, anovulation, and elevated serum androgen. Approximately 40% of these women have metabolic syndrome, marked by hyperinsulinemia, dyslipidemia, and insulin resistance. It has been suggested that developmental exposure to excess androgen contributes to the etiology of fertility disorders, including PCOS. To better define the role of the timing system in these disorders, we determined the effects of androgen-dependent developmental programming on clock gene expression in tissues of the metabolic and HPO axes. Female PERIOD2::luciferase (PER2::LUC) mice were exposed to androgen (dihydrotestosterone [DHT]) in utero (Days 16-18 of gestation) or for 9-10 wk (DHT pellet) beginning at weaning (pubertal androgen excess [PAE]). As expected, both groups of androgen-treated mice had disrupted estrous cycles. Analysis of PER2::LUC expression in tissue explants revealed that excess androgen produced circadian misalignment via tissue-dependent effects on phase distribution. In vitro treatment with DHT differentially affected the period of PER2::LUC expression in tissue explants and granulosa cells, indicating that androgen has direct and tissue-specific effects on clock gene expression that may account for the effects of developmental programming on the timing system. © 2015 by the Society for the Study of Reproduction, Inc.

[Cognitive plasticity in Alzheimer's disease patients receiving cognitive stimulation programs].

Science.gov (United States)

Zamarrón Cassinello, Ma Dolores; Tárraga Mestre, Luis; Fernández-Ballesteros, Rocío

2008-08-01

The main purpose of this article is to examine whether cognitive plasticity increases after cognitive training in Alzheimer's disease patients. Twenty six patients participated in this study, all of them diagnosed with mild Alzheimer's disease, 17 of them received a cognitive training program during 6 months, and the other 9 were assigned to the control group. Participants were assigned to experimental or control conditions for clinical reasons. In order to assess cognitive plasticity, all patients were assessed before and after treatment with three subtests from the "Bateria de Evaluación de Potencial de Aprendizaje en Demencias" [Assessment Battery of Learning Potential in Dementia] (BEPAD). After treatment, Alzheimer's disease patients improved their performance in all the tasks assessing cognitive plasticity: viso-spatial memory, audio-verbal memory and verbal fluency. However, the cognitive plasticity scores of the patients in the control group decreased. In conclusion, this study showed that cognitive stimulation programs can improve cognitive functioning in mildly demented patients, and patients who do not receive any cognitive interventions may reduce their cognitive functioning.

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications.

Science.gov (United States)

Lucas-Herald, Angela K; Alves-Lopes, Rheure; Montezano, Augusto C; Ahmed, S Faisal; Touyz, Rhian M

2017-07-01

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca 2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents

NARCIS (Netherlands)

Crespo, M.; van Dalum, Guus; Ferraldeschi, R.; Zafeiriou, Z.; Sideris, S.; Lorente, D.; Bianchini, D.; Rodrigues, D.N.; Rijsnaes, R.; Miranda, S.; Figueiredo, I.; Flohr, P.; Nowakowska, K.; de Bono, J.S.; Terstappen, Leonardus Wendelinus Mathias Marie; Attard, G.

2015-01-01

Background: Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated

Androgen imprinting of the brain in animal models and humans with intersex disorders: review and recommendations.

Science.gov (United States)

Hrabovszky, Zoltan; Hutson, John M

2002-11-01

Psychosexual development, gender assignment and surgical treatment in patients with intersex are controversial issues in the medical literature. Some groups are of the opinion that gender identity and sexual orientation are determined prenatally secondary to the fetal hormonal environment causing irreversible development of the nervous system. We reviewed the evidence in animal and human studies to determine the possible role of early postnatal androgen production in gender development. An extensive literature review was performed of data from animal experiments and human studies. RESULTS Many animal studies show that adding or removing hormonal stimulus in early postnatal life can profoundly alter gender behavior of the adult animal. Human case studies show that late intervention is unable to reverse gender orientation from male to female. Most studies have not permitted testing of whether early gender assignment and treatment as female with suppression/ablation of postnatal androgen production leads to improved concordance of the gender identity and sex of rearing. Animal studies support a role for postnatal androgens in brain/behavior development with human studies neither completely supportive nor antagonistic. Therefore, gender assignment in infants with intersex should be made with the possibility in mind that postnatal testicular hormones at ages 1 to 6 months may affect gender identity. A case-control study is required to test the hypothesis that postnatal androgen exposure may convert ambisexual brain functions to committed male behavior patterns.

Anxiety, depression in patients receiving chemotherapy for solid tumors

International Nuclear Information System (INIS)

Mansoor, S.; Jehangir, S.

2015-01-01

To determine the frequency of anxiety and depression in patients undergoing chemotherapy for solid tumors using Hospital Anxiety Depression Scale (HADS). Study Design: Cross sectional descriptive study. Place and Duration of Study: Out-patient department of Armed Forces Institute of Mental Health, Rawalpindi from June 2011 to December 2011. Methodology: Consecutive non probability sampling technique was used to select patients of age (25-70 years), male or female, who had received atleast 03 cycles of chemotherapy for solid tumors. Those with history of prior psychiatric illness, current use of psychotropic medication or psychoactive substance use, and any major bereavement in past one year were excluded from the study. After taking informed consent, relevant socio- demographic data was collected and HADS was administered. HADS-A cut off score of 7 was taken as significant anxiety while a HADS-D cut off score of 7 was taken as significant depression. Results: The total number of participants was 209. The mean age of patients was 42.9 years, with 55.5% males and 44.5% females. Overall 33/209 (15.8%) patients had anxiety while 56/209 (26.8%) were found to have depression. There was a higher frequency of anxiety and depression in younger patients (less than age 40 years), females, patients who were single or divorced, and patients receiving chemotherapy for pancreatic carcinoma. Conclusion: Patients undergoing chemotherapy suffer from considerable levels of anxiety and depression, thus highlighting the need for specialized interventions. (author)

The effect of oral contraception on cardiometabolic risk factors in women with elevated androgen levels.

Science.gov (United States)

Krysiak, Robert; Gilowska, Małgorzata; Okopień, Bogusław

2017-02-01

In unselected reproductive-aged women, use of combined estrogen-progestin oral contraceptive pills has been linked with an increased risk of vascular disease. The aim of this study was to investigate the effect of oral contraception on cardiometabolic risk factors in a population of women with hyperandrogenism. The study included 16 untreated women with elevated testosterone levels and 15 matched healthy women who were then treated with oral contraceptive pills containing ethinyl estradiol (30μg) and drospirenone (3mg). Plasma lipids, glucose homeostasis markers, circulating levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen and homocysteine, as well as urinary albumin-to-creatinine ratio (UACR) were assessed at baseline and after 12 weeks of treatment. Compared to healthy women, women with elevated androgen levels showed increased plasma levels of hsCRP, fibrinogen and homocysteine, as well as a higher value of UACR. Oral contraception reduced androgen levels only in hyperandrogenic women. In healthy women, ethinyl estradiol plus drospirenone increased plasma levels of insulin, hsCRP, fibrinogen and homocysteine, while in women with elevated androgen levels their effect was limited only to a small increase in hsCRP. Our results suggest that a deteriorating effect of oral contraceptive pills containing ethinyl estradiol and drospirenone in hyperandrogenic women is weaker than in healthy young women and that ethinyl estradiol/drospirenone combination therapy may be safely used in the former group of patients. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Anabolic Androgen-induced Intrahepatic Cholestasis Presented With Normal AND#947;-Glutamyl-Transpeptidase

Directory of Open Access Journals (Sweden)

Savvoula Savvidou

2014-04-01

A case report of a young male with remarkable jaundice due to acute anabolic androgen-induced cholestasis is presented. Interestingly, and #947;-glutamyl transpeptidase remained normal throughout the patient's diagnostic workup. Histopathology was indicative of pure, and ldquo;bland and rdquo; intrahepatic cholestasis with minimal inflammation but significant fibrosis. The patient was successfully treated with ursodeoxycholic acid and glucocorticosteroids. The significance of normal and #947;-glutamyl transpeptidase along with the histopathological findings and the possible pathophysiological mechanisms are finally discussed. [J Interdiscipl Histopathol 2014; 2(2.000: 98-103

Clinical Outcomes from Androgen Signaling-directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

Science.gov (United States)

Smith, Matthew R; Saad, Fred; Rathkopf, Dana E; Mulders, Peter F A; de Bono, Johann S; Small, Eric J; Shore, Neal D; Fizazi, Karim; Kheoh, Thian; Li, Jinhui; De Porre, Peter; Todd, Mary B; Yu, Margaret K; Ryan, Charles J